PF-05175157: A Comprehensive Profile of a Dual ACC Inhibitor from Preclinical Promise to Clinical Discontinuation

Executive Summary

PF-05175157 is an investigational, orally bioavailable small molecule developed as a potent, dual inhibitor of Acetyl-CoA Carboxylase isoforms 1 and 2 (ACC1 and ACC2). The therapeutic rationale for this mechanism was ambitious and scientifically robust: by simultaneously inhibiting both isoforms, the compound was designed to deliver a powerful, two-pronged attack on disordered lipid metabolism. Inhibition of the cytosolic ACC1 isoform was intended to block de novo lipogenesis (DNL), the synthesis of new fatty acids, a key pathway in diseases like nonalcoholic steatohepatitis (NASH) and acne vulgaris. Concurrently, inhibition of the mitochondrial ACC2 isoform was expected to relieve the suppression of carnitine palmitoyltransferase I (CPT-1), thereby promoting fatty acid β-oxidation (FAO) and increasing the utilization of existing lipids, a highly desirable effect for treating Type 2 Diabetes Mellitus (T2DM).

This elegant mechanism of action translated successfully from preclinical models into early-phase human trials. Clinical studies demonstrated robust target engagement, evidenced by a significant and dose-dependent reduction in DNL in healthy volunteers. This provided clear proof of mechanism and validated the therapeutic hypothesis in humans, marking a significant scientific achievement. However, the program's trajectory was abruptly halted by the emergence of a critical safety signal during multi-dose studies. An asymptomatic, dose-dependent, and reversible thrombocytopenia (reduction in platelet count) was identified as the dose-limiting toxicity.

Subsequent investigations revealed this adverse effect was not due to an off-target activity but was a direct consequence of the drug's intended mechanism occurring in an unintended tissue—an "on-target, off-tissue" toxicity. ACC inhibition within the bone marrow was found to impair the maturation of megakaryocytes by disrupting the DNL-dependent synthesis of phospholipids required for platelet formation. This toxicity was species-specific, appearing in humans and non-human primates but not in the standard rodent and canine models used for regulatory toxicology, highlighting a critical translational gap in preclinical safety assessment. The systemic nature of PF-05175157 meant that this on-target toxicity was inseparable from its therapeutic effect.

Ultimately, the development of PF-05175157 was terminated. However, the program should not be viewed as a complete failure. The deep mechanistic understanding gained from its clinical challenges provided invaluable insights. The precise elucidation of the cause of thrombocytopenia provided a clear blueprint for a next-generation approach: a molecule that could retain potent ACC inhibition within the liver (the primary site of action for metabolic disease) while minimizing exposure to the bone marrow. This led directly to the rational design of a liver-targeted successor, PF-05221304, which exploited hepatic uptake transporters. The story of PF-05175157 thus serves as a powerful case study in modern drug development, illustrating the complexities of target biology, the limitations of preclinical models, and the iterative nature of science, where understanding the reasons for failure is often the most critical step toward future success.

Molecular Identity and Physicochemical Characteristics

A comprehensive understanding of any drug candidate begins with its fundamental chemical identity and physical properties, which dictate its behavior in biological systems and its suitability for pharmaceutical development. PF-05175157 is a well-characterized small molecule with a distinct chemical structure and a profile largely optimized for oral administration.

Nomenclature and Identifiers

To ensure unambiguous identification across scientific literature, regulatory filings, and chemical databases, PF-05175157 is cataloged under a variety of systematic names and unique identifiers.

• Primary Name: The compound is most commonly referred to by its Pfizer research code, PF-05175157.[1]
• Systematic (IUPAC) Name: Its formal chemical name is 1'-(2-methyl-1H-1,3-benzodiazole-6-carbonyl)-1-(propan-2-yl)-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-7-one.[1] Minor variations in nomenclature, such as the use of "1'-(2-methyl-3H-benzimidazole-5-carbonyl)-1-propan-2-ylspiro[4,6-dihydroindazole-5,4'-piperidine]-7-one," are also reported but describe the same chemical entity.[1]
• Database Identifiers: The molecule is extensively cross-referenced in major public and commercial databases, providing a robust digital footprint. Key identifiers include:
• CAS Number: 1301214-47-0.[1]
• DrugBank ID: DB12096.[1]
• PubChem CID: 52934180.[8]
• ChEMBL ID: CHEMBL3359265.[1]
• UNII (Unique Ingredient Identifier): P826WR56FI.[1]

Chemical Structure and Classification

The architecture of PF-05175157 reveals a complex, multi-ring system designed for specific interactions with its biological target while maintaining properties conducive to drug development.

• Molecular Formula: The empirical formula for PF-05175157 is .[1]
• Structural Representations: The molecule's connectivity is precisely defined by standardized line notations:
• SMILES: CC1=NC2=C(N1)C=C(C=C2)C(=O)N3CCC4(CC3)CC5=C(C(=O)C4)N(N=C5)C(C)C.[1]
• InChIKey: BDXXSFOJPYSYOC-UHFFFAOYSA-N.[1]
• Chemical Taxonomy: Based on its constituent functional groups and ring systems, PF-05175157 belongs to the class of organic compounds known as N-benzoylpiperidines.[4] It is a spiropiperidine derivative, characterized by a spirocyclic junction between the indazole and piperidine rings.[12] The structure incorporates several key pharmacophoric elements, including a benzimidazole moiety, a pyrazole ring fused to a cyclohexenone, and an aryl alkyl ketone functional group, all of which contribute to its binding affinity and overall chemical nature.[4]

Physicochemical Properties and Drug-Likeness

The physicochemical profile of PF-05175157 reflects a deliberate medicinal chemistry effort to create a molecule with favorable "drug-like" properties suitable for oral delivery. These properties govern its absorption, distribution, and ability to reach its target within the body. The molecular structure was not merely optimized for potency but was carefully engineered to possess characteristics required for a successful oral drug. This rational design was subsequently validated by preclinical bioavailability data showing effective absorption in animal models.[5] A summary of its key properties is presented in Table 1.

Property	Value	Source(s)
IUPAC Name	1'-(2-methyl-1H-1,3-benzodiazole-6-carbonyl)-1-(propan-2-yl)-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-7-one	DrugBank, PubChem 1
CAS Number	1301214-47-0	DrugBank, PubChem 1
DrugBank ID	DB12096	DrugBank 4
PubChem CID	52934180	PubChem 8
Molecular Formula		DrugBank, PubChem 1
Molecular Weight (Average)	405.5 g/mol	PubChem, DrugBank 1
Molecular Weight (Monoisotopic)	405.216475129 Da	DrugBank 4
SMILES	CC1=NC2=C(N1)C=C(C=C2)C(=O)N3CCC4(CC3)CC5=C(C(=O)C4)N(N=C5)C(C)C	DrugBank, PubChem 1
InChIKey	BDXXSFOJPYSYOC-UHFFFAOYSA-N	PubChem, Cayman Chem 1
logP	1.72 - 2.24	Chemaxon, ALOGPS 4
Water Solubility	0.0529 mg/mL	ALOGPS 4
pKa (Strongest Acidic)	11.36	Chemaxon 4
pKa (Strongest Basic)	6.01	Chemaxon 4
Hydrogen Bond Acceptor Count	4	Chemaxon, PubChem 1
Hydrogen Bond Donor Count	1	Chemaxon, PubChem 1
Rotatable Bond Count	2	Chemaxon, PubChem 1
Topological Polar Surface Area	83.88	Chemaxon 4
Rule of Five Compliance	Yes	Chemaxon 4

The molecule's moderate lipophilicity (logP between 1.72 and 2.24) and low number of rotatable bonds (2) are attributes that favor good oral absorption and membrane permeability.[4] Its pKa values predict that it will be predominantly in a neutral state at physiological pH, further aiding its ability to passively diffuse across cellular barriers.[4] While its aqueous solubility is low, this is a common feature of orally administered small molecules and is often addressed through formulation; its high solubility in organic solvents like DMSO and ethanol facilitates its use in research and formulation development.[3]

Crucially, PF-05175157 adheres to Lipinski's Rule of Five and the Ghose Filter, two widely used computational filters that predict a high likelihood of oral bioavailability.[4] These rules are based on molecular properties such as molecular weight (<500 Da), lipophilicity (logP <5), and the number of hydrogen bond donors (<5) and acceptors (<10). The compound's compliance with these guidelines indicates a successful outcome of the medicinal chemistry design phase, aimed at producing a developable drug candidate.

Pharmacodynamics: Mechanism of Action and Biological Target

The therapeutic potential of PF-05175157 is rooted in its specific and potent interaction with Acetyl-CoA Carboxylase (ACC), a critical gatekeeper enzyme in cellular lipid metabolism. The decision to target ACC with a dual inhibitor reflects a sophisticated understanding of metabolic biochemistry and a clear therapeutic hypothesis for treating a range of metabolic disorders.

The Acetyl-CoA Carboxylase (ACC) Target

Acetyl-CoA Carboxylase is a biotin-dependent ligase that catalyzes the first committed and rate-limiting step in the biosynthesis of fatty acids: the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA.[4] This reaction is central to the regulation of energy balance, controlling whether the cell stores energy as fat or utilizes it for fuel. In mammals, two distinct isoforms of ACC exist, encoded by different genes (ACACA and ACACB), with specialized roles and tissue distributions.[10]

• ACC1 (ACACA): This isoform is found primarily in the cytoplasm of lipogenic tissues, such as the liver, adipose tissue, and lactating mammary glands.[2] The malonyl-CoA produced by ACC1 serves as the primary building block for de novo lipogenesis (DNL), providing the two-carbon units that are assembled by fatty acid synthase (FASN) into long-chain fatty acids like palmitate.[2] Inhibition of ACC1 is therefore a direct strategy to reduce the synthesis of new fats.
• ACC2 (ACACB): This isoform is predominantly localized to the outer mitochondrial membrane, particularly in tissues with high rates of fatty acid oxidation, including skeletal muscle, heart, and liver.[2] The malonyl-CoA generated by ACC2 functions as a potent allosteric inhibitor of carnitine palmitoyltransferase I (CPT-1).[2] CPT-1 is the enzyme responsible for transporting long-chain fatty acyl-CoAs into the mitochondrial matrix, a prerequisite for their breakdown via β-oxidation (FAO). By inhibiting ACC2, the suppressive brake on CPT-1 is released, thereby promoting the burning of fatty acids for energy.

Therapeutic Rationale of Dual Inhibition

The strategy behind developing a dual ACC1/ACC2 inhibitor like PF-05175157 was to achieve a powerful, synergistic effect on lipid metabolism. By simultaneously blocking ACC1 and ACC2, the drug was hypothesized to induce a profound metabolic shift:

1. Inhibit Lipid Synthesis: By blocking ACC1, the drug reduces the supply of malonyl-CoA for DNL, directly decreasing the production of new fatty acids and triglycerides in the liver.
2. Promote Lipid Oxidation: By blocking ACC2, the drug lowers mitochondrial malonyl-CoA levels, disinhibiting CPT-1 and increasing the rate of fatty acid oxidation in muscle and liver.

This combined action of decreasing lipid storage while increasing lipid utilization was considered an ideal approach for treating complex metabolic diseases like T2DM and NASH, which are characterized by both excessive fat accumulation and impaired fat oxidation.[2]

Inhibition Profile and Potency

PF-05175157 demonstrated potent inhibitory activity against both ACC isoforms across multiple species in cell-free enzymatic assays. This potent, broad-spectrum activity was the cornerstone of its pharmacological profile. The reported half-maximal inhibitory concentrations () establish it as a low-nanomolar inhibitor, as detailed in Table 2.

Target Enzyme	IC₅₀ (nM)	Source(s)
Human ACC1	27.0 ± 2.7	Cayman Chem, Selleckchem 3
	98	R&D Systems, Tocris 6
Human ACC2	33.0 ± 4.1	Cayman Chem, Selleckchem 3
	45	R&D Systems, Tocris 6
Rat ACC1	23.5 ± 1.1	Cayman Chem, Selleckchem 3
Rat ACC2	50.4 ± 2.6	Cayman Chem, Selleckchem 3

While there are minor variations in the reported absolute potency values, likely due to differences in experimental assay conditions between suppliers, the data consistently confirm that PF-05175157 is a potent inhibitor of both ACC1 and ACC2, with similar activity against human and rat enzymes. This cross-species potency was a key factor enabling the translation of findings from preclinical rat models to human clinical studies.

Mechanistically, PF-05175157 is a spiropiperidine derivative that functions as an inhibitor of the carboxyltransferase (CT) domain of ACC.[12] This distinguishes it from other classes of ACC inhibitors, such as firsocostat, which are allosteric modulators that bind to the biotin carboxylase (BC) dimerization site.[18]

The very nature of its pharmacodynamic profile—potent, systemic, dual inhibition of a fundamental metabolic enzyme—represents a high-reward but also high-risk strategy. The therapeutic hypothesis was predicated on achieving a powerful, systemic shift in lipid metabolism by targeting ACC in key metabolic tissues like the liver and muscle. However, ACC is expressed in numerous other tissues where DNL plays essential physiological roles.[10] A potent inhibitor with good oral bioavailability and systemic distribution will inevitably inhibit the enzyme wherever it is expressed. This creates an inherent risk of on-target toxicity in non-target tissues. The subsequent clinical findings of thrombocytopenia, driven by ACC inhibition in bone marrow megakaryocytes, were a direct manifestation of this intrinsic risk.[20] The drug's greatest strength—its potent and systemic mechanism of action—was simultaneously the source of its dose-limiting toxicity, making the separation of therapeutic benefit from adverse risk exceptionally challenging without fundamentally altering the drug's distribution.

Preclinical Pharmacology and Pharmacokinetics

Before advancing to human trials, PF-05175157 underwent extensive preclinical evaluation to confirm that its enzymatic potency translated into meaningful biological effects in cellular and animal models and to characterize its pharmacokinetic profile. The results from these studies were highly encouraging and provided a strong rationale for clinical development.

In Vitro and In Vivo Pharmacodynamic Effects

Experiments in isolated cells and whole animals confirmed that PF-05175157 effectively engaged its target and produced the desired downstream metabolic consequences.

• Cellular Activity: The drug's effect was first validated in a relevant cell-based system. In primary rat hepatocytes, PF-05175157 inhibited the formation of malonyl-CoA, the direct product of the ACC enzyme, in a concentration-dependent manner. The measured half-maximal effective concentration () was approximately 30 nM, a value in excellent agreement with its enzymatic potency () against the rat ACC1 isoform (24 nM).[3] This demonstrated that the compound could effectively penetrate cells and inhibit its intracellular target.
• Animal Models: The promising cellular data were successfully replicated in in vivo studies using rats. Following a single oral dose, PF-05175157 induced robust and dose-dependent metabolic changes consistent with dual ACC inhibition:
• Target Engagement in Key Tissues: The drug led to profound reductions in malonyl-CoA levels in both the liver (up to an 89% decrease) and skeletal muscle (up to a 76% decrease). This confirmed that the drug reached and inhibited both ACC1 (liver) and ACC2 (muscle) in vivo.[3]
• Inhibition of De Novo Lipogenesis: Consistent with the reduction in hepatic malonyl-CoA, PF-05175157 strongly inhibited hepatic DNL, reducing the incorporation of radiolabeled acetate into lipids by as much as 82%.[3]
• Stimulation of Fatty Acid Oxidation: The drug caused a significant reduction in the whole-body respiratory exchange ratio (RER). The RER is the ratio of carbon dioxide produced to oxygen consumed and serves as an indicator of metabolic fuel source. A lower RER signifies a greater reliance on fat oxidation for energy. This finding provided strong evidence that inhibition of ACC2 was successfully promoting whole-body fatty acid utilization.[3]

Exploratory Antiviral Activity

In addition to its primary metabolic effects, PF-05175157 was found to possess intriguing antiviral properties. Many viruses, including flaviviruses, co-opt host cell metabolic pathways, particularly fatty acid synthesis, to support their replication by providing lipids for viral membranes and energy. A study investigated whether inhibiting this host pathway could serve as an antiviral strategy. Treatment with PF-05175157 was shown to inhibit the multiplication of several medically important flaviviruses, including West Nile virus (WNV), dengue virus, and Zika virus, in cell culture.[2] Furthermore, in a mouse model of WNV infection, PF-05175157 administration reduced the viral load in both serum and the kidney, suggesting a potential therapeutic role for ACC inhibitors in treating viral infections and associated pathologies, such as the chronic kidney disease linked to persistent WNV infection.[13]

Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

The pharmacokinetic studies in animals revealed an ADME profile that was highly favorable for an oral drug candidate.

• Absorption and Bioavailability: PF-05175157 was well-absorbed after oral administration. It demonstrated good oral bioavailability in dogs (54% at a 3 mg/kg dose) and rats (40% at 3 mg/kg).[5] Interestingly, at a higher oral dose of 50 mg/kg in rats, the bioavailability increased to 106%, suggesting that a saturable first-pass clearance mechanism was at play.[5]
• Metabolism and Clearance: The compound exhibited high metabolic stability. In vitro experiments using liver microsomes from rats, dogs, and humans showed minimal to no metabolism.[5] It was also stable in incubations with intact human hepatocytes. Further investigation with recombinant human enzymes identified it as a minimal substrate for cytochrome P450 isoforms CYP3A4 and CYP3A5, indicating that these enzymes play only a minor role in its elimination.[5] This metabolic stability translated to low plasma clearance when the drug was administered intravenously to rats, dogs, and monkeys.[5]

Taken together, the preclinical data presented a compelling, though ultimately misleading, case for the clinical development of PF-05175157. The in vitro enzymatic potency translated seamlessly to cellular activity, which in turn led to robust, dose-dependent target engagement and the desired pharmacodynamic effects in key metabolic tissues of a relevant animal model. This was coupled with a favorable ADME profile indicative of a viable oral drug. Standard regulatory toxicology studies in rodents and dogs showed no major safety signals that would have prevented its advancement. The decision to proceed to human trials was therefore not only logical but strongly supported by a comprehensive preclinical package. The eventual clinical failure highlights a profound disconnect between this successful preclinical validation and the ultimate human outcome. It serves as a powerful case study on the limitations of preclinical models to fully recapitulate human-specific biology. The physiological role of the DNL pathway in platelet production is non-essential in rodents but critical in primates.[20] Thus, the very success of the preclinical program in confirming the drug's potent systemic action inadvertently masked the critical translational flaw that would only become apparent in human subjects.

Clinical Development Program and Investigated Indications

Buoyed by a strong preclinical data package, PF-05175157 advanced into a multi-faceted clinical development program. The drug reached Phase II trials, exploring its utility in several indications where dysregulated lipid metabolism is a core pathogenic feature, before development was ultimately halted due to safety concerns.[1] The program was designed to test the central therapeutic hypothesis in different clinical contexts, primarily Type 2 Diabetes Mellitus (T2DM) and acne vulgaris.

Indication I: Type 2 Diabetes Mellitus (T2DM)

T2DM was the lead indication for PF-05175157, leveraging the dual ACC inhibition mechanism to simultaneously address hepatic steatosis (via DNL inhibition) and insulin resistance in muscle (via increased FAO).

• Phase I Studies: A series of Phase I trials were successfully completed in healthy volunteers and patients with T2DM. These studies were designed to establish the safety, tolerability, pharmacokinetic profile, and proof of mechanism in humans.[22] Key trials included NCT01537497, NCT01396161, and NCT01433380. The results from these early studies were promising, confirming that oral administration of PF-05175157 led to a robust reduction in DNL and an increase in whole-body fatty acid utilization, thereby validating the drug's mechanism of action in a clinical setting.[2]
• Drug-Drug Interaction (DDI) Studies: As part of the standard early development process, dedicated trials were conducted to assess the potential for PF-05175157 to interact with other commonly prescribed medications. Given the preclinical finding that it was a minimal substrate for CYP3A4/5, its potential to affect or be affected by other drugs metabolized by this pathway was a key question.[5]
• One study (NCT01807377 / NCT01757756) evaluated its interaction with midazolam, a sensitive CYP3A4 substrate.[22]
• Another study (NCT01469468) assessed the effect of repeated dosing of PF-05175157 on the pharmacokinetics of a single dose of simvastatin, another widely used drug metabolized by CYP3A4.[22]
• Phase II Studies: Based on the positive Phase I data, the program advanced to Phase IIa to evaluate efficacy and safety over a longer duration. At least three such trials were initiated in patients with T2DM, but all were ultimately terminated before completion, coinciding with the emergence of the dose-limiting hematologic toxicity.[25] These trials were designed to explore the drug's utility in different therapeutic settings:
• NCT01792635: A 6-week, randomized, double-blind, placebo-controlled study of PF-05175157 as a monotherapy.[25]
• NCT02053103: A 6-week study evaluating PF-05175157 as an add-on therapy for patients already taking metformin.[25]
• NCT02053116: A 6-week study assessing PF-05175157 in combination with the SGLT2 inhibitor canagliflozin in patients on a background of metformin therapy.[25]

Indication II: Acne Vulgaris

The clinical program also explored the utility of PF-05175157 in dermatology, specifically for the treatment of acne vulgaris.

• Scientific Rationale: The pathogenesis of acne is closely linked to the overproduction of sebum by sebaceous glands. Sebum is a complex lipid mixture, and its synthesis is highly dependent on the DNL pathway within sebocytes. The therapeutic hypothesis was that by inhibiting ACC, PF-05175157 could directly reduce sebum production at its source, offering a novel, non-hormonal, systemic treatment for acne.[27]
• Human Proof-of-Concept Study: This hypothesis was tested in a mechanistic study involving healthy volunteers. The results were compelling: oral administration of PF-05175157 at a dose of 200 mg twice daily for two weeks was well-tolerated and resulted in a substantial reduction in facial sebum production, with decreases ranging from 49% to 66% compared to baseline and placebo.[27] This study provided strong clinical validation for the role of DNL in human sebum production and the potential of ACC inhibition as a therapeutic strategy.
• Phase II Trial: Following the successful proof-of-concept study, a Phase II trial (NCT01953421) was planned to evaluate the efficacy and safety of PF-05175157 in adults with moderate to severe acne vulgaris. However, this study was withdrawn prior to patient enrollment.[28] This withdrawal was almost certainly a direct consequence of the systemic safety issues being identified in the parallel T2DM program, which precluded further development of the compound for any indication.

The comprehensive clinical development plan for PF-05175157 is summarized in Table 3. The pattern of trial termination across multiple indications strongly suggests that a systemic, indication-agnostic issue was responsible for halting the program.

ClinicalTrials.gov ID	Indication	Phase	Status	Brief Description/Purpose	Key Drugs
NCT01396161	T2DM / Healthy Volunteers	1	Completed	Evaluate safety, tolerability, PK, and PD	PF-05175157 22
NCT01469468	Healthy Volunteers	1	Completed	Assess DDI with simvastatin	PF-05175157, Simvastatin 22
NCT01807377	Healthy Volunteers	1	Completed	Assess DDI with midazolam	PF-05175157, Midazolam 22
NCT01792635	T2DM	2	Terminated	6-week monotherapy safety and PD study	PF-05175157 25
NCT02053103	T2DM	2	Terminated	6-week add-on to metformin safety/effect study	PF-05175157 25
NCT02053116	T2DM	2	Terminated	6-week add-on to metformin/canagliflozin study	PF-05175157 25
NCT01953421	Acne Vulgaris	2	Withdrawn	Efficacy and safety study in moderate to severe acne	PF-05175157 28

Critical Safety Findings and Program Termination

Despite demonstrating clear proof of mechanism in early clinical trials, the development of PF-05175157 was ultimately derailed by a critical safety finding that proved insurmountable for a systemically distributed drug. This adverse event was not an off-target effect but was intrinsically linked to the drug's intended pharmacology, providing a stark lesson in the challenges of targeting fundamental metabolic pathways.

Emergence of Thrombocytopenia

During multi-dose Phase I and the initial stages of Phase II clinical studies, a consistent, dose-limiting toxicity emerged: an asymptomatic, reversible, and dose-dependent reduction in circulating platelet counts, a condition known as thrombocytopenia.[20] While the reductions were not typically severe enough to cause spontaneous bleeding, they represented a significant safety liability that would preclude chronic administration, which is necessary for treating conditions like T2DM and NASH. The effect was observed to be reversible, with platelet counts returning to baseline after cessation of the drug.[20] This dose-dependent and reversible nature strongly implicated the drug as the causative agent and was the primary reason for the termination of the entire clinical development program.[21]

Mechanism of Hematologic Toxicity

Intensive investigation into the cause of the thrombocytopenia revealed a fascinating and instructive biological mechanism. The toxicity was determined to be an "on-target, off-tissue" effect, meaning it was caused by the intended mechanism of action (ACC inhibition) but was occurring in an unintended tissue (the bone marrow).[21]

The production of platelets, a process known as thrombopoiesis, involves the maturation of large precursor cells in the bone marrow called megakaryocytes. A critical step in this maturation is the massive expansion of an internal membrane reservoir known as the demarcation membrane system (DMS). This intricate network of membranes provides the raw material for the megakaryocyte to shed thousands of new platelets into the bloodstream.[20] The synthesis of the vast quantities of phospholipids required for this membrane expansion is heavily reliant on the de novo lipogenesis pathway, for which ACC1 is the rate-limiting enzyme.

By systemically inhibiting ACC1, PF-05175157 inadvertently starved megakaryocytes of the essential lipid building blocks (particularly phosphatidylcholine) needed to construct the DMS. This impairment of megakaryocyte maturation led to a decrease in the production of new platelets, resulting in a lower count in the peripheral circulation.[20]

The Species-Specific Discrepancy

One of the most critical lessons from the PF-05175157 program was the failure of standard preclinical toxicology studies to predict this adverse event. The thrombocytopenia was observed clinically in humans and was subsequently replicated in non-human primate models.[20] However, this effect was conspicuously absent in the regulatory toxicology studies conducted in rodents (rats) and non-rodents (dogs).[20]

This striking species-specific difference implies that the fundamental biological reliance of platelet production on the DNL pathway is a characteristic of primates but not of lower mammals like rodents and canines. This finding has profound implications for drug development, as it highlights a significant limitation of traditional preclinical safety models for certain biological pathways. It underscores that even a well-executed preclinical safety package cannot guarantee the absence of unforeseen toxicities in humans, particularly when the drug target is involved in fundamental cellular processes that may have evolved different dependencies across species.

The elucidation of this on-target, mechanism-based toxicity was a pivotal moment. It transformed the problem from what might have been an idiosyncratic issue with the PF-05175157 molecule into a predictable, target-class liability. It became clear that any potent, systemically distributed ACC inhibitor, regardless of its chemical structure, would likely carry the same risk of causing thrombocytopenia in humans. This realization invalidated the entire therapeutic approach of systemic ACC inhibition from a safety perspective. Consequently, the only viable path forward for the ACC inhibitor class was not to design a better systemic inhibitor, but to fundamentally change the strategy of inhibition itself. This strategic pivot, forced by the failure of PF-05175157, was the direct intellectual catalyst for the development of tissue-selective, next-generation compounds.

Legacy and the Development of a Successor: The Rise of PF-05221304

The termination of the PF-05175157 program was not an endpoint but a critical turning point. The deep mechanistic understanding of its dose-limiting toxicity provided a clear and actionable set of design principles for a next-generation compound. The legacy of PF-05175157 is therefore not one of failure, but of providing the crucial knowledge that enabled a more sophisticated and rational approach to targeting ACC.

From Failure to Rational Redesign

The well-defined, mechanism-based nature of the thrombocytopenia offered a clear path forward. The challenge was not to create a more potent or selective inhibitor, but to solve a drug distribution problem: how to maintain potent ACC inhibition in the target organ (the liver) while simultaneously minimizing drug exposure in the site of toxicity (the bone marrow).[21] This objective became the central tenet of the successor program.

The Liver-Targeting Hypothesis

To achieve this separation of therapeutic efficacy from systemic toxicity, a "hepatoselective" or "liver-targeting" strategy was devised.[21] The goal was to design a molecule that would be preferentially taken up and concentrated in the liver, the primary site of DNL and a key organ in metabolic diseases like NASH. The chosen approach was to engineer molecules that could act as substrates for Organic Anion Transporting Polypeptides (OATPs). These are uptake transporters highly expressed on the surface of hepatocytes but not on bone marrow cells. By incorporating a carboxylic acid moiety into the chemical scaffold of the ACC inhibitors, the new compounds were designed to be actively transported into the liver via OATPs. This would lead to high drug concentrations at the therapeutic site of action while keeping systemic plasma concentrations—and therefore exposure to peripheral tissues like the bone marrow—relatively low.[21]

PF-05221304: A Safer Successor

This rational design effort culminated in the discovery of the clinical candidate PF-05221304.[21] This molecule was also a potent dual ACC1/ACC2 inhibitor, but with the crucial addition of OATP substrate properties.

Preclinical evaluation of PF-05221304 validated the liver-targeting hypothesis. In animal models, it demonstrated the desired asymmetrical tissue distribution, leading to selective inhibition of DNL in the liver.[21] Most importantly, when tested in non-human primates—the species that had proven to be predictive of the platelet toxicity—PF-05221304 showed a considerably improved safety margin against platelet reduction compared to its predecessor, PF-05175157.[21] This provided strong evidence that the liver-targeting strategy had successfully uncoupled the desired hepatic effect from the unwanted hematologic toxicity. This improved safety profile allowed PF-05221304 to advance into clinical trials, representing the next chapter in the development of ACC inhibitors.

Conclusion and Forward Outlook

The developmental history of PF-05175157 provides a complete and compelling narrative of the modern drug discovery and development process, encapsulating both its immense potential and its inherent risks. From a scientific standpoint, the molecule was a success. It was a potent, orally bioavailable compound that robustly validated the therapeutic hypothesis of dual ACC inhibition in humans, demonstrating significant target engagement and a powerful effect on de novo lipogenesis. The program successfully translated a complex biochemical concept into a tangible pharmacodynamic effect in a clinical setting.

However, its clinical failure serves as a seminal case study in drug development, offering several critical lessons. It is a powerful illustration of "on-target, off-tissue" toxicity, where the intended mechanism of action, when applied systemically, produces an unacceptable adverse effect in a non-target organ. Furthermore, it starkly highlights the limitations of inter-species translation in preclinical safety assessment. The discovery that the physiological dependence of platelet production on DNL is a primate-specific trait underscores the fact that even the most rigorous preclinical toxicology programs using standard animal models cannot eliminate the risk of unforeseen human-specific toxicities.

Ultimately, the legacy of PF-05175157 is a positive and constructive one. The deep mechanistic understanding gained from dissecting its failure was not a dead end but a catalyst for innovation. It transformed a specific drug's problem into a general target-class challenge, forcing a strategic evolution away from simple systemic inhibition. This knowledge directly enabled the rational design of a more sophisticated and safer class of liver-targeted ACC inhibitors, exemplified by PF-05221304. The story of PF-05175157 is a testament to the iterative and resilient nature of pharmaceutical science, where rigorously understanding the reasons for failure is often the most critical step toward achieving future therapeutic success. It has paved the way for continued exploration of ACC as a vital therapeutic target for a range of metabolic diseases, but with a newfound appreciation for the importance of tissue-selective drug delivery.

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