Comprehensive Monograph on Sarpogrelate (DB12163)

Executive Summary

Sarpogrelate is a selective serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor antagonist with a unique pharmacological profile characterized by a dual mechanism of action involving both the inhibition of platelet aggregation and the suppression of vasoconstriction. Developed primarily in Japan and South Korea, it has established a significant clinical role in the management of ischemic symptoms associated with chronic arterial occlusive diseases. This monograph provides a comprehensive analysis of Sarpogrelate, synthesizing available data on its chemical properties, pharmacology, clinical efficacy, safety, and comparative positioning against other antiplatelet agents.

Key findings from extensive clinical investigation reveal Sarpogrelate's efficacy in improving hemodynamic parameters and symptoms in patients with peripheral arterial disease (PAD). Furthermore, it has demonstrated vasculoprotective effects in coronary artery disease (CAD), particularly in populations with comorbid diabetes mellitus, where it improves not only vascular function but also underlying metabolic and inflammatory markers. A pivotal aspect of Sarpogrelate's clinical profile is its safety, most notably a significantly lower risk of bleeding complications compared to aspirin, as demonstrated in the large-scale S-ACCESS trial for secondary stroke prevention. While it did not prove non-inferior to aspirin in preventing recurrent infarction in the overall population, its favorable safety profile and a signal of potential benefit in diabetic patients highlight its importance as a strategic therapeutic alternative.

The drug's pharmacokinetic profile is defined by rapid absorption, peripheral selectivity with minimal blood-brain barrier penetration, and metabolism to a long-acting active metabolite, M-1, which sustains its therapeutic effect. A significant potential for drug-drug interactions exists via potent inhibition of the cytochrome P450 2D6 (CYP2D6) enzyme. This report concludes that Sarpogrelate is a valuable therapeutic agent, not as a universally superior antiplatelet, but as a specialized tool for personalized medicine. Its optimal clinical niche is in patients with a high bleeding risk, those with diabetes-associated vasculopathy, or individuals intolerant to other agents like cilostazol, positioning it as a cornerstone of therapy for specific, well-defined patient populations, primarily within East Asian markets.

Introduction: A Profile of a Selective 5-HT2A Receptor Antagonist

Sarpogrelate is a synthetic small molecule drug that occupies a distinct position within the therapeutic armamentarium for vascular disorders.[1] Developed by Mitsubishi Chemical and subsequently Mitsubishi Tanabe Pharma Corporation under the developmental codes MCI-9042 and LS-187,118, Sarpogrelate has been extensively researched and utilized, particularly in Japan and South Korea, where it is a well-established treatment for conditions characterized by impaired blood flow.[3] It is classified pharmacologically as a platelet aggregation inhibitor and a selective serotonin 5-HT2A receptor antagonist.[1]

The therapeutic rationale for Sarpogrelate is rooted in the critical role of serotonin (5-hydroxytryptamine, 5-HT) in the pathophysiology of thrombosis and vascular disease. Serotonin, released from activated platelets, is a potent mediator of further platelet aggregation and vasoconstriction through its action on 5-HT2A receptors located on platelets and vascular smooth muscle cells.[4] In atherosclerotic disease, this pathway contributes significantly to thrombus formation and the reduction of blood flow, leading to ischemic symptoms. By selectively blocking the 5-HT2A receptor, Sarpogrelate directly counteracts these pathological processes, offering a targeted mechanism to improve circulation and prevent thrombotic events.[4]

This monograph provides a comprehensive, expert-level review of Sarpogrelate, synthesizing data from preclinical studies, clinical trials, and pharmacovigilance. It will deliver a detailed analysis of the drug's chemical and physicochemical properties, its complete pharmacological profile including both pharmacodynamics and pharmacokinetics, a thorough evaluation of the clinical evidence supporting its efficacy across a range of vascular pathologies, a meticulous assessment of its safety and drug interaction profile, and a critical comparative analysis against other standard-of-care antiplatelet agents. The focus will be on elucidating the drug's unique clinical positioning, primarily informed by its extensive history of use and research in Asian populations.[4]

Chemical Identity and Physicochemical Properties

3.1. Nomenclature, Identifiers, and Formulations

The precise identification of a pharmaceutical agent is foundational to its study and clinical use. Sarpogrelate is the internationally recognized generic name for this compound.[1] Its systematic International Union of Pure and Applied Chemistry (IUPAC) name is 4-[1-(dimethylamino)-3-[2-(3-methoxyphenyl)ethyl]phenoxy]propan-2-yl]oxy-4-oxobutanoic acid.[1]

For unambiguous identification in scientific and regulatory databases, Sarpogrelate is assigned several unique identifiers. The Chemical Abstracts Service (CAS) Registry Number for the free base form of the molecule is 125926-17-2.[1] The drug is most commonly formulated as a hydrochloride salt to enhance its pharmaceutical properties, and this salt form is identified by CAS Number 135159-51-2.[6] Other key global identifiers include its DrugBank Accession Number (DB12163), PubChem Compound ID (5160), ChEMBL ID (CHEMBL52939), and FDA Unique Ingredient Identifier (UNII 19P708E787).[1]

Throughout its development and in the literature, Sarpogrelate is also referred to by its developmental codes, MCI-9042 and LS-187,118.[3] It is marketed primarily under the trade name Anplag®.[2]

Sarpogrelate is administered orally and is available in multiple formulations designed to meet different clinical needs. These include immediate-release (IR) tablets, typically available in 50 mg and 100 mg strengths, which are usually administered three times daily.[13] To improve patient convenience and adherence, a controlled-release (CR) or sustained-release (SR) 300 mg tablet has also been developed for once-daily administration.[15] The development of both IR and CR formulations reflects a strategic approach to optimize the drug's pharmacokinetic profile for chronic use, balancing the need for rapid action with the benefits of sustained therapeutic levels and simplified dosing regimens. The use of the hydrochloride salt form is a critical aspect of its formulation, as it confers enhanced water solubility and chemical stability compared to the free base, which is essential for reliable oral absorption.[10]

3.2. Molecular Structure and Physicochemical Characteristics

Sarpogrelate is a synthetic organic small molecule classified chemically as a stilbenoid and a hemisuccinate.[1] The molecular formula of the free base is

C24​H31​NO6​, corresponding to an average molecular weight of 429.513 g/mol and a monoisotopic mass of 429.215137722 Da.[3] The hydrochloride salt has the molecular formula

C24​H32​ClNO6​ and an average molecular weight of 465.97 g/mol.[9]

The molecule's two-dimensional structure is unambiguously described by its Simplified Molecular Input Line Entry System (SMILES) string: CN(C)CC(COC1=CC=CC=C1CCC2=CC(=CC=C2)OC)OC(=O)CCC(=O)O.[3] Its constitution and connectivity are further defined by its International Chemical Identifier (InChI) and InChIKey, which are

InChI=1S/C24H31NO6/c1-25(2)16-21(31-24(28)14-13-23(26)27)17-30-22-10-5-4-8-19(22)12-11-18-7-6-9-20(15-18)29-3/h4-10,15,21H,11-14,16-17H2,1-3H3,(H,26,27) and FFYNAVGJSYHHFO-UHFFFAOYSA-N, respectively.[2]

The physicochemical properties of Sarpogrelate are crucial determinants of its pharmacokinetic behavior, including its absorption, distribution, metabolism, and excretion (ADME). These properties, consolidated in Table 1, indicate that Sarpogrelate is a moderately lipophilic molecule that adheres to Lipinski's Rule of Five, suggesting good potential for oral bioavailability.[2] The molecule contains one hydrogen bond donor and seven hydrogen bond acceptors (Lipinski), with a topological polar surface area of 85.3

A˚2.[2] Its predicted partition coefficient (XLogP or logP) values range from 1.12 to 3.57, indicating moderate lipid solubility, which facilitates passage across cell membranes but is not so high as to cause poor aqueous solubility or excessive sequestration in adipose tissue.[3] The presence of both a basic tertiary amine (

pKa≈8.15) and an acidic carboxylic acid (pKa≈3.78) means the molecule's ionization state is highly dependent on pH, a factor that influences its absorption in the gastrointestinal tract and its solubility.[18] The poor solubility of the hydrochloride salt in certain organic solvents, such as acetone, has been noted as a relevant factor in its chemical synthesis and purification processes.[6]

Table 1: Key Identifiers and Physicochemical Properties of Sarpogrelate

Property	Value (Sarpogrelate Free Base)	Value (Sarpogrelate HCl)	Source Snippet(s)
IUPAC Name	4-[1-dimethylamino)-3-[2-(3-methoxyphenyl)ethyl]phenoxy]propan-2-yl]oxy-4-oxobutanoic acid	4-{[1-(dimethylamino)-3-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}propan-2-yl]oxy}-4-oxobutanoic acid hydrochloride	1
CAS Number	125926-17-2	135159-51-2	1
DrugBank ID	DB12163	DBSALT002147	8
UNII	19P708E787	FQN8N8QP1B	1
Molecular Formula	C24​H31​NO6​	C24​H32​ClNO6​	8
Molecular Weight	429.51 g/mol	465.97 g/mol	8
logP	1.12 - 3.28	3.57	2
pKa (Strongest Acidic)	3.78	3.78	18
pKa (Strongest Basic)	8.15	8.15	18
Polar Surface Area	85.3 A˚2	85.3 A˚2	2
H-Bond Donors	1	1	2
H-Bond Acceptors	7 (Lipinski) / 6 (Chemaxon)	6	1
Rotatable Bonds	13 - 14	14	1
Water Solubility	Not Available	0.0109 mg/mL	19

Pharmacological Profile

4.1. Pharmacodynamics

The pharmacodynamic actions of Sarpogrelate are centered on its highly selective and potent antagonism of the serotonin 5-HT2A receptor, complemented by important pleiotropic effects that contribute to its overall therapeutic profile in vascular diseases.

Primary Mechanism: Selective Serotonin 5-HT2A Receptor Antagonism

The core mechanism of Sarpogrelate is its function as a competitive antagonist at the 5-HT2A receptor.[4] In the vasculature, serotonin released from dense granules of activated platelets acts as a powerful local hormone. By binding to 5-HT2A receptors on the surface of adjacent platelets, it triggers a signaling cascade that leads to a conformational change in the glycoprotein IIb/IIIa receptor, promoting platelet aggregation and thrombus growth. Simultaneously, serotonin binding to 5-HT2A receptors on vascular smooth muscle cells (VSMCs) induces potent vasoconstriction.[4] Sarpogrelate effectively blocks both of these pathological processes by preventing serotonin from binding to its receptor, thereby exerting both antiplatelet and vasodilatory effects. This dual action is fundamental to its clinical utility in improving ischemic symptoms, such as pain, coldness, and ulceration, that arise from chronic arterial occlusion.[6]

Receptor Binding Profile and Selectivity

Sarpogrelate's efficacy and safety are significantly influenced by its high selectivity for the 5-HT2A receptor subtype. In vitro binding assays have quantified its high affinity, with reported pKi values of 8.52, Ki values of 8.39 nM, and Kd values as low as 0.2 nM for the human 5-HT2A receptor.[9] While it also acts as an antagonist at the 5-HT2B and 5-HT2C receptor subtypes, its affinity for these is substantially lower—approximately one to two orders of magnitude less than for the 5-HT2A receptor, with pKi values of 6.57 and 7.43, respectively.[3]

Crucially, Sarpogrelate demonstrates negligible binding affinity for other major receptor families, including other serotonin receptor subtypes (5-HT1, 5-HT3, 5-HT4), adrenergic receptors (α1, α2, and β), histamine receptors (H1, H2), and muscarinic receptors (M3).[9] This high degree of selectivity is a key pharmacological feature, as it minimizes the potential for off-target effects that could lead to undesirable side effects, distinguishing it from less selective serotonergic agents.

Pleiotropic Effects: Inhibition of Vascular Smooth Muscle Proliferation and Anti-inflammatory Actions

Beyond its immediate antiplatelet and vasodilatory actions, Sarpogrelate exhibits additional beneficial effects on the vessel wall. A critical secondary mechanism is its ability to inhibit the proliferation of VSMCs induced by serotonin.[9] This anti-proliferative action is highly relevant to the prevention of neointimal hyperplasia, a primary driver of restenosis following endovascular procedures like angioplasty and stenting.[23] By mitigating this response, Sarpogrelate may contribute to the long-term patency of treated vessels.

Furthermore, a growing body of evidence suggests that Sarpogrelate possesses anti-inflammatory and anti-oxidative properties.[4] In a clinical study involving diabetic patients with stable angina, treatment with Sarpogrelate was associated with significant reductions in markers of inflammation (high-sensitivity C-reactive protein, hsCRP) and oxidative stress (thiobarbituric acid reactive substances, TBARS).[24] These pleiotropic effects may contribute to its ability to retard the progression of atherosclerosis and ameliorate the vasculopathic complications of diabetes, positioning it as more than a simple antiplatelet agent.[7]

4.2. Pharmacokinetics

The clinical application and dosing of Sarpogrelate are governed by its pharmacokinetic profile, which is characterized by rapid absorption, peripheral distribution, extensive metabolism to a key active metabolite, and a notable influence of food and formulation on its bioavailability.

Absorption, Bioavailability, and the Influence of Food and Formulation

Following oral administration, Sarpogrelate in its immediate-release (IR) formulation is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations (Cmax) are typically reached within a short timeframe, approximately 0.5 to 0.7 hours post-dose.[16] A study in healthy male subjects receiving a 100 mg IR dose reported a mean Cmax of 856.3 ng/mL at 0.7 hours.[25] The controlled-release (CR) 300 mg formulation, when taken in a fasted state, exhibits a similarly rapid time to peak concentration (Tmax) of about 0.5 hours.[16]

A critical factor influencing the pharmacokinetics of the CR formulation is the presence of food. Administration with a high-fat meal significantly alters its absorption profile, delaying the Tmax to approximately 4.0 hours and substantially reducing both the Cmax and the total drug exposure (AUC).[16] Geometric mean ratios (fed vs. fasted) for Cmax and AUC were found to be 0.4868 and 0.7394, respectively, indicating a decrease of over 50% in peak concentration and over 25% in total exposure.[26] This pronounced food effect is believed to be due to the drug's pH-dependent dissolution characteristics.[27] These findings underscore the importance of consistent administration with respect to meals to ensure predictable therapeutic effects.

Distribution and Peripheral Selectivity

A defining feature of Sarpogrelate's pharmacokinetics is its limited ability to cross the blood-brain barrier (BBB).[3] This property results in the drug being peripherally selective. Animal studies in rats have demonstrated that peak concentrations of Sarpogrelate in the brain and spinal cord are approximately 50-fold lower than those observed in the plasma, representing only about 2% of the systemic concentration.[3] This peripheral selectivity has profound clinical implications. Despite being a potent modulator of the serotonin system, a major neurotransmitter system in the central nervous system (CNS), Sarpogrelate's inability to achieve significant concentrations in the brain minimizes its potential for direct, centrally-mediated side effects such as sedation or mood alterations. This characteristic is fundamental to its favorable tolerability profile. The numerous documented interactions involving CNS depression are therefore more likely a result of pharmacodynamic potentiation of other co-administered CNS-active drugs rather than a primary effect of Sarpogrelate itself.

Metabolism, Active Metabolites, and Cytochrome P450 Interactions

Sarpogrelate undergoes significant metabolism, primarily into an active metabolite known as M-1.[25] The pharmacokinetic profile of this metabolite is crucial to the drug's overall therapeutic action. While the parent Sarpogrelate molecule has a very short elimination half-life, the M-1 metabolite has a much longer half-life of approximately 4.4 hours.[25] This extended duration of the active metabolite provides a sustained pharmacological effect that persists long after the parent drug has been cleared from circulation. This dynamic explains how a drug with such a short half-life can be effective with a three-times-daily IR regimen and how a once-daily CR formulation can be developed to maintain therapeutic coverage.

In terms of drug-drug interactions, in vitro studies have identified a significant interaction potential via the cytochrome P450 system. Both Sarpogrelate and its M-1 metabolite are potent inhibitors of the CYP2D6 enzyme.[25] This suggests a high likelihood of clinically relevant pharmacokinetic interactions when Sarpogrelate is co-administered with drugs that are substrates of CYP2D6 (e.g., metoprolol, codeine, certain antidepressants). However, Sarpogrelate and M-1 do not appear to be time-dependent inactivators of CYP enzymes and show no significant inhibition of other major isoforms, including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5.[25]

Excretion and Elimination Half-Life

The elimination of Sarpogrelate is rapid. For the IR formulation, the parent drug has an elimination half-life (t1/2​) of approximately 0.7 to 0.8 hours.[16] The CR formulation extends the apparent half-life to about 3.2 hours under fasting conditions, though this is shortened to 1.45 hours when taken with food, reflecting the altered absorption kinetics.[16] After metabolism, Sarpogrelate and the M-1 metabolite undergo further glucuronide conjugation, and these metabolites are primarily excreted via the bile.[25]

Table 2: Pharmacokinetic Parameters of Sarpogrelate (IR/CR Formulations) and its Active Metabolite

Parameter	Sarpogrelate (100mg IR)	Sarpogrelate (300mg CR, Fasted)	Sarpogrelate (300mg CR, Fed)	Metabolite M-1 (from 100mg IR)	Source Snippet(s)
Tmax​ (hr)	0.7	0.5 - 0.75	4.0	0.9	16
Cmax​ (ng/mL)	856.3	~Comparable to 3 doses of IR	Reduced by >50% vs. Fasted	49.3	16
t1/2​ (hr)	0.8	3.23	1.45	4.4	16
AUC	Not specified	Slightly higher than 3 doses of IR	Reduced by ~26% vs. Fasted	Not specified	16

Clinical Efficacy in Vascular Pathologies

5.1. Management of Peripheral Arterial Disease (PAD) and Chronic Arterial Occlusion

The primary approved indication for Sarpogrelate is for the improvement of various ischemic symptoms associated with chronic arterial occlusion, a condition often manifesting as peripheral arterial disease (PAD).[4] Clinical evidence robustly supports its efficacy in this setting. Patients with PAD often suffer from debilitating symptoms such as intermittent claudication, rest pain, coldness in the extremities, and ischemic ulcers. Sarpogrelate addresses the underlying pathophysiology by improving blood flow through its dual antiplatelet and vasodilatory actions.[14]

A meta-analysis incorporating data from 12 randomized controlled trials (RCTs) provided strong evidence of its clinical benefits. The analysis concluded that treatment with Sarpogrelate led to statistically significant improvements in key objective measures compared to conventional treatments. These included an increase in the ankle-brachial index (ABI), a primary hemodynamic indicator of lower extremity perfusion, and enhanced dorsalis pedis artery blood flow.[28] Furthermore, Sarpogrelate significantly improved functional capacity, as measured by an increase in pain-free walking distance (PFWD).[28] Beyond these hemodynamic and functional improvements, the drug was also shown to modulate the inflammatory state associated with atherosclerosis, significantly reducing levels of systemic inflammatory markers like high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6).[28]

In the specific context of patients undergoing percutaneous endovascular interventions (EVIs) for femoropopliteal arterial lesions, Sarpogrelate has been evaluated as part of a dual antiplatelet therapy (DAPT) regimen. A prospective, multicenter, randomized clinical trial directly compared a regimen of aspirin plus Sarpogrelate (100 mg three times daily) against the standard-of-care regimen of aspirin plus clopidogrel (75 mg once daily). The results demonstrated that the Sarpogrelate-based therapy was a comparable antithrombotic regimen to the clopidogrel-based therapy in preventing restenosis at 6 months, with similar rates of target lesion revascularization (TLR) and other safety outcomes.[23]

5.2. Role in Ischemic Heart Disease: Coronary Microcirculation and Angina

Sarpogrelate has been investigated for its potential benefits in patients with ischemic heart disease, including coronary artery disease (CAD) and angina pectoris.[6] The rationale for its use extends beyond preventing epicardial coronary thrombosis to improving the function of the coronary microcirculation, which plays a critical role in myocardial perfusion. Clinical studies have shown that Sarpogrelate can indeed improve coronary microcirculatory function in patients with established CAD.[6]

The therapeutic value of Sarpogrelate appears to be particularly pronounced in patients with comorbid diabetes mellitus, a group known for extensive vascular disease and endothelial dysfunction. A study involving 30 patients with type 2 diabetes and stable angina randomized them to receive either Sarpogrelate (300 mg/day) or control for 12 months.[24] The Sarpogrelate group experienced significant improvements across a range of parameters. Vascular function was enhanced, as evidenced by improvements in flow-mediated dilation (FMD) and pulse wave velocity (PWV). Patients' functional capacity improved, with a significant prolongation of exercise tolerance time. Importantly, Sarpogrelate also favorably modulated key metabolic and inflammatory markers, significantly decreasing insulin resistance (as measured by HOMA-IR), inflammation (hsCRP), and oxidative stress (TBARS).[24] These findings suggest that Sarpogrelate offers multifaceted vasculoprotective benefits in this high-risk population that go beyond simple antiplatelet activity.

5.3. Secondary Prevention of Cerebrovascular Events

The potential role of Sarpogrelate in the secondary prevention of ischemic stroke was rigorously evaluated in the Sarpogrelate-Aspirin Comparative Clinical Study for Efficacy and Safety in Secondary Prevention of Cerebral Infarction (S-ACCESS).[32] This large-scale, randomized, double-blind trial enrolled 1510 Japanese patients with a recent cerebral infarction and compared the efficacy and safety of Sarpogrelate (100 mg three times daily) with that of low-dose aspirin (81 mg daily) over a mean follow-up of 1.59 years.[32]

The primary efficacy endpoint was the recurrence of cerebral infarction. The study failed to demonstrate that Sarpogrelate was non-inferior to aspirin. The event rate was numerically higher in the Sarpogrelate group (6.09%/year) compared to the aspirin group (4.86%/year), resulting in a hazard ratio (HR) of 1.25 (95% CI, 0.89 to 1.77), which crossed the prespecified non-inferiority margin of 1.33.[32]

Despite the disappointing efficacy outcome, the S-ACCESS trial yielded a critical finding regarding safety. The overall incidence of bleeding events was significantly lower in the Sarpogrelate group (89 events, 11.9%) compared to the aspirin group (131 events, 17.3%; p<0.01).[32] A post-hoc subgroup analysis suggested a potential differential effect in patients with diabetes mellitus. In this subgroup, the hazard ratio for recurrent cerebral infarction was reversed, favoring Sarpogrelate (HR 0.87; 95% CI, 0.48 to 1.60), although this interaction was not statistically significant.[34] This finding, combined with the superior bleeding profile, suggests that Sarpogrelate may represent a useful treatment option for certain patient populations, particularly those with diabetes at a high risk of bleeding.

5.4. Investigational Applications in Diabetic Complications

Given the promising signals observed in diabetic subgroups across various trials, Sarpogrelate has been specifically investigated for its role in mitigating diabetic complications, most notably diabetic nephropathy.[1] The drug has completed Phase 4 clinical trials for this indication, including the SONATA study (NCT01869881), which was designed to evaluate the effect of Sarpogrelate on nephropathy in patients with type 2 diabetes.[36]

Mechanistic studies provide a strong rationale for these investigations. Sarpogrelate has been shown to reduce urinary albumin excretion, a key marker of kidney damage in diabetes, as well as to lower both urinary and plasma levels of thromboxane A2, a potent vasoconstrictor and platelet aggregator implicated in the pathogenesis of diabetic nephropathy.[6] These effects, combined with its broader anti-inflammatory and endothelial-protective actions, suggest a potential role in slowing the progression of renal disease in diabetic patients. The consistent pattern of benefit seen in patients with diabetes across studies of the heart, brain, and kidneys points toward a specific vasculoprotective phenotype for Sarpogrelate in this complex patient population, where its mechanism appears to target several downstream consequences of hyperglycemia on the vasculature.

Safety, Tolerability, and Risk Management

6.1. Adverse Drug Reaction Profile

Sarpogrelate is generally well-tolerated, with a predictable profile of adverse effects. A comprehensive understanding of both common and serious adverse reactions is essential for safe clinical use.

Common Adverse Events

The most frequently reported side effects associated with Sarpogrelate therapy are generally mild to moderate in severity and often transient.[4] These primarily include:

• Gastrointestinal Disturbances: Nausea, vomiting, diarrhea, and constipation are common complaints.[4]
• Neurological Symptoms: Dizziness and headaches are also frequently reported.[4]
• Dermatological Reactions: Skin reactions such as rash, redness, papules, itching, erythema, and hives may occur.[4]
• Hemorrhagic Events: Minor bleeding, such as epistaxis (nose bleeding) and subcutaneous bleeding (bruising), can be observed due to the drug's antiplatelet activity.[14]

Serious Adverse Events

While rare, several potentially serious adverse events have been documented and require immediate medical evaluation and discontinuation of the drug. These include:

• Major Bleeding: The most significant risk is major hemorrhage. This can manifest as cerebral bleeding (presenting with severe headache, nausea, vomiting) or gastrointestinal bleeding (presenting with abdominal pain, hematemesis, or melena).[14]
• Hematologic Disorders: Severe hematologic abnormalities have been reported, including thrombocytopenia (a significant decrease in platelet count, leading to increased bleeding risk) and agranulocytosis (a severe reduction in white blood cells, presenting with symptoms like sore throat, headache, and high fever).[14]
• Hepatotoxicity: Liver dysfunction and jaundice have been observed. Patients should be monitored for signs such as general malaise, loss of appetite, and yellowing of the skin or sclera (icterus).[14]

6.2. Contraindications, Warnings, and Precautions

To ensure patient safety, the use of Sarpogrelate is restricted in certain populations and requires careful consideration in others.

Contraindications

Sarpogrelate is strictly contraindicated in the following situations:

• Active Bleeding: Patients with active pathological bleeding, such as those with hemophilia, capillary fragility, active gastrointestinal ulcers, urinary tract bleeding, hemoptysis, or vitreous bleeding, should not receive the drug.[4]
• Hypersensitivity: A known history of allergic reaction or hypersensitivity to Sarpogrelate or any of its components is a contraindication.[4]
• Severe Hepatic Impairment: Because the drug is metabolized in the liver and its metabolites are excreted in the bile, it is contraindicated in patients with severe hepatic dysfunction due to the risk of drug accumulation and increased toxicity.[4]

Warnings and Precautions

Special caution should be exercised in the following clinical scenarios:

• Bleeding Risk: Patients with a history of bleeding disorders or those taking concomitant medications that interfere with hemostasis (e.g., anticoagulants, other antiplatelet agents, NSAIDs) are at an increased risk of bleeding and require close monitoring.[4]
• Pregnancy and Lactation: The safety of Sarpogrelate during pregnancy and breastfeeding has not been firmly established, and its use should be carefully weighed against potential risks.[13]
• Medication Reconciliation: Patients should be advised to inform their healthcare providers of all medications they are taking, including over-the-counter drugs and dietary supplements, to avoid potential drug interactions.[13]

6.3. Analysis of Drug-Drug Interactions

Sarpogrelate has a high potential for clinically significant drug-drug interactions, which can be broadly categorized by their underlying mechanism: pharmacodynamic potentiation of bleeding or CNS depression, and pharmacokinetic inhibition of CYP2D6. The extensive list of potential interactions necessitates a structured approach to risk assessment and management.[8]

Pharmacodynamic Interactions - Increased Bleeding Risk

The most critical interactions are those that potentiate the risk of hemorrhage. Co-administration of Sarpogrelate with any other agent that impairs hemostasis creates an additive or synergistic effect. This high-risk category includes:

• Anticoagulants: Warfarin, acenocoumarol, and direct oral anticoagulants (DOACs) like apixaban and rivaroxaban.[8]
• Other Antiplatelet Agents: Glycoprotein IIb/IIIa inhibitors (abciximab), ADP receptor antagonists (clopidogrel), and others like anagrelide and cilostazol.[8]
• Thrombolytic Agents: Alteplase and anistreplase.[8]
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Aceclofenac, ibuprofen, naproxen, and others that inhibit platelet function.[8]

Combination therapy with these agents should be avoided or undertaken with extreme caution and intensive monitoring for signs of bleeding.

Pharmacodynamic Interactions - Increased CNS Depression

An extensive list of drugs has been identified as potentially causing increased CNS depression when combined with Sarpogrelate.[8] As Sarpogrelate itself has minimal CNS penetration, this risk is primarily due to an additive effect where Sarpogrelate fails to counteract the depressant effects of the co-administered drug. This category includes benzodiazepines (alprazolam), opioids (alfentanil), tricyclic antidepressants (amineptine), first-generation antihistamines (azelastine), muscle relaxants (baclofen), and many others. While the risk from any single combination may be moderate, clinicians should be highly vigilant when prescribing Sarpogrelate to patients on multiple CNS-active medications.

Pharmacokinetic Interactions - The Role of CYP2D6

In vitro data have established that both Sarpogrelate and its active metabolite, M-1, are potent inhibitors of the cytochrome P450 2D6 enzyme.[25] This creates a high potential for pharmacokinetic interactions by impairing the metabolism of co-administered drugs that are CYP2D6 substrates. This could lead to elevated plasma concentrations and increased toxicity of the substrate drug. Clinically relevant CYP2D6 substrates include certain beta-blockers (metoprolol, carvedilol), antiarrhythmics (flecainide, propafenone), antidepressants (amitriptyline, fluoxetine, paroxetine), and antipsychotics (risperidone, haloperidol). The opioid analgesic codeine is also a notable example, as its conversion to the active metabolite morphine is dependent on CYP2D6; co-administration with Sarpogrelate could lead to therapeutic failure. Prescribers must carefully review a patient's medication list for CYP2D6 substrates before initiating Sarpogrelate.

Serotonin Syndrome

A theoretical risk of serotonin syndrome, a potentially life-threatening condition caused by excessive serotonergic activity, exists when Sarpogrelate is combined with other serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs). While noted as a rare possibility, clinicians should be aware of the symptoms (e.g., mental status changes, autonomic hyperactivity, neuromuscular abnormalities).[4]

Table 4: Clinically Significant Drug-Drug Interactions and Management Recommendations

Interacting Drug Class	Example Drugs	Mechanism of Interaction	Potential Clinical Outcome	Risk Level	Management Recommendation
Anticoagulants	Warfarin, Apixaban, Rivaroxaban	Pharmacodynamic (additive antithrombotic effect)	Major hemorrhage	High	Co-administration is generally contraindicated or requires expert consultation and intensive monitoring.
Antiplatelet Agents	Aspirin, Clopidogrel, Abciximab	Pharmacodynamic (additive antiplatelet effect)	Major hemorrhage	High	Use DAPT only when clinically indicated (e.g., post-EVI) and for the shortest necessary duration. Monitor closely for bleeding.
NSAIDs	Ibuprofen, Naproxen, Aceclofenac	Pharmacodynamic (inhibition of platelet cyclooxygenase)	Gastrointestinal bleeding, systemic hemorrhage	Moderate to High	Avoid chronic co-administration if possible. If necessary, use with caution and consider gastroprotective agents.
CYP2D6 Substrates	Metoprolol, Codeine, Fluoxetine	Pharmacokinetic (inhibition of CYP2D6 metabolism)	Increased concentration and toxicity of the substrate drug; therapeutic failure for prodrugs like codeine.	High	Avoid combination if possible. If necessary, consider dose reduction of the CYP2D6 substrate and monitor for adverse effects or lack of efficacy.
CNS Depressants	Benzodiazepines, Opioids, Antihistamines	Pharmacodynamic (additive CNS depressant effect)	Excessive sedation, respiratory depression, impaired cognitive/motor function	Moderate	Use with caution. Advise patients of the potential for increased drowsiness and to avoid activities requiring mental alertness.
Serotonergic Agents	SSRIs (e.g., Sertraline), MAOIs	Pharmacodynamic (potential for excessive serotonergic activity)	Serotonin Syndrome	Low/Theoretical	Monitor for symptoms of serotonin syndrome, although the risk is considered low.

Comparative Assessment and Clinical Positioning

The clinical value of Sarpogrelate is best understood not in isolation, but in comparison to other widely used antiplatelet and vasoactive agents. Its unique profile of efficacy, safety, and tolerability defines its specific niche in a crowded therapeutic landscape.

7.1. Versus Aspirin: Balancing Efficacy and Bleeding Risk

The S-ACCESS trial provides the most direct and robust comparison between Sarpogrelate and aspirin for the secondary prevention of ischemic stroke.[32] In terms of efficacy, aspirin proved to be the superior agent in the overall study population, as Sarpogrelate failed to meet the pre-specified criteria for non-inferiority.[34] However, the safety data told a different story. Sarpogrelate was associated with a statistically significant and clinically meaningful reduction in the incidence of bleeding events compared to aspirin.[32] This fundamental trade-off between efficacy and safety is central to Sarpogrelate's positioning.

The data suggests a specific patient profile where this trade-off favors Sarpogrelate. In a post-hoc analysis of the S-ACCESS trial, the efficacy gap between the two drugs appeared to narrow or even reverse in patients with diabetes mellitus.[34] Another study focusing on primary prevention in high- or very-high-risk diabetic patients without established atherosclerotic cardiovascular disease (ASCVD) found that Sarpogrelate was associated with a net clinical benefit, driven primarily by a significant reduction in overall bleeding events compared to aspirin.[33] Therefore, Sarpogrelate is positioned as a compelling alternative to aspirin, particularly in patients with a high baseline bleeding risk or in the specific context of primary prevention in high-risk diabetic populations where minimizing harm from bleeding is a primary concern.

7.2. Versus Clopidogrel: Mechanistic Distinctions and Clinical Equivalence

Sarpogrelate and clopidogrel represent two distinct pharmacological approaches to platelet inhibition. Clopidogrel is an irreversible antagonist of the P2Y12 adenosine diphosphate (ADP) receptor, a key pathway in platelet activation and aggregation. In contrast, Sarpogrelate targets the serotonin 5-HT2A receptor pathway and, importantly, also inhibits the proliferation of vascular smooth muscle cells (VSMCs), an effect not shared by clopidogrel.[23] This anti-proliferative action is theoretically advantageous for preventing the neointimal hyperplasia that underlies in-stent restenosis.

Despite these mechanistic differences, clinical outcomes appear to be largely equivalent in the setting of PAD. A randomized trial in patients undergoing femoropopliteal endovascular intervention found that a dual antiplatelet regimen of aspirin plus Sarpogrelate was comparable and non-inferior to the standard regimen of aspirin plus clopidogrel for the prevention of restenosis.[23] From a pharmacokinetic standpoint, Sarpogrelate possesses a much shorter elimination half-life compared to clopidogrel's active metabolite.[42] This could offer a significant advantage in the perioperative setting, as Sarpogrelate could be discontinued much closer to the time of a planned surgery, reducing the duration of unprotected thrombotic risk while still minimizing intraoperative bleeding. Consequently, Sarpogrelate is positioned as a mechanistically distinct but clinically equivalent alternative to clopidogrel for patients with PAD, with a potential advantage in perioperative management.

7.3. Versus Cilostazol: Comparative Tolerability and Effects on Endothelial Function

Both Sarpogrelate and cilostazol are used to treat symptoms of PAD, such as intermittent claudication, but they operate through different mechanisms. Cilostazol is a phosphodiesterase-III inhibitor that increases intracellular cyclic AMP, leading to both antiplatelet effects and vasodilation.[43]

In terms of efficacy for improving vascular health, the two agents appear comparable. A head-to-head study in young male smokers demonstrated that both Sarpogrelate and cilostazol were equally effective at improving endothelial dysfunction, as measured by flow-mediated dilatation.[45] Retrospective studies of triple antiplatelet therapy (aspirin, clopidogrel, plus a third agent) in patients after percutaneous coronary intervention (PCI) have suggested that Sarpogrelate-containing regimens may offer comparable or even superior outcomes in preventing major adverse cardiac and cerebrovascular events (MACCE) compared to cilostazol-containing regimens, without an increased risk of bleeding.[46]

The most significant differentiator between the two drugs is tolerability. Cilostazol is notoriously associated with headaches, which can be severe enough to lead to treatment discontinuation. The comparative study confirmed this, showing a significantly higher incidence and intensity of headaches in the cilostazol group, which led to patient dropouts.[45] Sarpogrelate was much better tolerated in this regard. This positions Sarpogrelate as a valuable alternative for patients with PAD who require treatment for claudication but are intolerant to the side effects of cilostazol.

Table 5: Comparative Profile of Sarpogrelate, Aspirin, Clopidogrel, and Cilostazol

Feature	Sarpogrelate	Aspirin	Clopidogrel	Cilostazol
Primary Mechanism	Selective 5-HT2A Receptor Antagonist	Irreversible COX-1/2 Inhibitor	Irreversible P2Y12 ADP Receptor Antagonist	Phosphodiesterase-III Inhibitor
Key Pleiotropic Effects	Inhibits VSMC proliferation; anti-inflammatory; anti-oxidative	Anti-inflammatory (at higher doses)	Anti-inflammatory	Vasodilatory; Inhibits VSMC proliferation
Efficacy in Stroke (Secondary Prevention)	Not non-inferior to Aspirin	Standard of care	Standard of care (alternative to Aspirin)	Not a primary agent
Efficacy in PAD	Effective for symptoms & post-EVI (comparable to Clopidogrel)	Modest benefit for symptoms; used for systemic risk reduction	Standard of care post-EVI	Effective for intermittent claudication
Primary Safety Concern	Bleeding (less than Aspirin)	GI and intracranial bleeding	Bleeding	Bleeding
Key Tolerability Issue	Generally well-tolerated; GI upset	Gastritis, ulcers	Dyspepsia, rash	Headache, palpitations, diarrhea
Niche/Advantage	Lower bleeding risk vs. Aspirin; benefits in diabetics; better tolerability vs. Cilostazol; short half-life for perioperative management	Broadly effective and inexpensive	Potent P2Y12 inhibition; established efficacy post-PCI/ACS	Strong evidence for improving walking distance in claudication

Developmental and Regulatory History

8.1. Discovery (MCI-9042) and Preclinical Evaluation

Sarpogrelate was discovered and developed by the Japanese pharmaceutical company Mitsubishi Chemical, which later became part of Mitsubishi Tanabe Pharma Corporation.[5] During its research and development phase, the compound was known by the internal codes MCI-9042 and LS-187,118.[3] The initial synthesis methods for the sarpogrelate hydrochloride salt were disclosed in early patents, such as US4485258.[6]

Preclinical development programs established the core pharmacological properties of the molecule. These foundational studies demonstrated its potent and highly selective antagonist activity at the 5-HT2A receptor.[9] In various animal models, MCI-9042 was shown to effectively inhibit serotonin-induced platelet aggregation and thrombus formation.[7] In addition to its antithrombotic effects, these early studies also identified its ability to inhibit the proliferation of vascular smooth muscle cells, a key finding that suggested a potential role in preventing the long-term consequences of vascular injury, such as restenosis.[7]

8.2. Regulatory Approvals and Market Presence in Asia

Following successful preclinical and clinical development, Sarpogrelate has been approved for clinical use, but its market presence is geographically concentrated. The drug has been primarily developed for and marketed in East Asian countries, most notably Japan and South Korea, where it has been an established therapy for several decades.[4] It was first approved in Japan in 1993 for the treatment of ischemic symptoms associated with chronic arterial occlusive disease.[46] It is marketed under the brand name Anplag®.[2]

The regulatory bodies overseeing its approval in these key markets are the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the Ministry of Food and Drug Safety (MFDS) in South Korea.[48] While the general regulatory frameworks for drug approval in these countries are well-defined, specific English-language approval documents or review reports for Sarpogrelate were not identified within the available resources.[49]

The drug's highest global development phase is "Marketed" for arterial occlusive disorders.[5] However, development programs for other major cardiovascular indications, including cerebral infarction and myocardial infarction, have been discontinued.[5] This strategic decision likely reflects the outcomes of key clinical trials, such as the S-ACCESS study, which failed to demonstrate non-inferiority to established global standards like aspirin for secondary stroke prevention. This has effectively solidified Sarpogrelate's position as a valuable but specialized agent for specific vascular conditions rather than a broad-spectrum antithrombotic for all forms of ASCVD. This regional concentration of its clinical use means that the vast majority of clinical experience and trial data has been generated in Japanese and Korean patient populations, a factor that should be considered when extrapolating its effects to other ethnic groups.

Conclusion and Expert Recommendations

Sarpogrelate (DB12163) is a well-characterized, selective 5-HT2A receptor antagonist that has established a clear and valuable clinical role through its dual mechanism of antiplatelet and vasculoprotective actions. Its pharmacological profile is distinguished by high receptor selectivity and peripheral action, which contribute to a favorable tolerability profile. While it is not a universally superior antithrombotic agent when compared to global standards of care like aspirin and clopidogrel across all indications, Sarpogrelate has successfully carved out a distinct and important clinical niche.

The synthesis of available evidence indicates that Sarpogrelate's primary value lies not in superior potency, but in its unique risk-benefit profile tailored to specific patient populations. Its most compelling attribute is a significantly lower risk of bleeding complications compared to aspirin, making it a preferred option in patients where hemorrhagic risk is a major concern. Furthermore, a consistent signal of enhanced benefit has been observed in patients with diabetes mellitus, where its pleiotropic effects on inflammation, oxidative stress, and endothelial function appear to address the multifaceted nature of diabetic vasculopathy. In the management of PAD, it stands as a clinically equivalent alternative to clopidogrel and a better-tolerated alternative to cilostazol.

Based on this comprehensive review, Sarpogrelate should be considered a sophisticated tool for personalized antithrombotic therapy. Its use is most strongly supported in patients with PAD, particularly those with comorbid diabetes, a high bleeding risk, or intolerance to other agents.

Expert Recommendations for Future Research

To further clarify and expand the clinical role of Sarpogrelate, the following areas of research are recommended:

1. Dedicated Outcomes Trial in Diabetic Polyvascular Disease: A large-scale, prospective, randomized controlled trial is warranted to definitively assess the efficacy and safety of Sarpogrelate versus a standard-of-care agent (e.g., aspirin or clopidogrel) specifically in patients with diabetes and established PAD and/or CAD. The primary endpoint should be a composite of major adverse cardiovascular and limb events (MACLE), with major bleeding as a key safety endpoint.
2. Perioperative Management Studies: Prospective studies should be designed to formally evaluate the clinical benefits of Sarpogrelate's short pharmacokinetic half-life in the perioperative setting. Comparing a strategy of late discontinuation of Sarpogrelate versus early discontinuation of clopidogrel in patients undergoing elective non-cardiac surgery could provide high-value evidence to guide clinical practice.
3. Pharmacogenomic Investigations: Given the well-established impact of CYP2C19 genetics on clopidogrel response, research into potential pharmacogenomic markers influencing Sarpogrelate's efficacy or safety is warranted. Investigating the impact of CYP2D6 polymorphisms, in particular, could help personalize its use and mitigate the risk of drug-drug interactions.
4. Long-Term Restenosis Prevention: While short-term studies have shown non-inferiority to clopidogrel after EVI, longer-term trials (2-3 years) are needed to determine if Sarpogrelate's unique anti-proliferative mechanism translates into a durable benefit in preventing late restenosis and the need for repeat revascularization.

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