PCO-371: A Comprehensive Review of an Investigational Oral PTHR1 Agonist

1. Introduction to PCO-371

1.1. Overview and Rationale for Development

PCO-371 (also known as PCO371 or PC-0371) is an orally bioavailable, non-peptide small molecule that was developed as an agonist for the parathyroid hormone receptor type 1 (PTHR1).[1] The primary therapeutic motivation behind its development was to address disorders related to parathyroid hormone (PTH) function, with a particular focus on hypoparathyroidism. Hypoparathyroidism is a rare endocrine condition characterized by deficient endogenous PTH production, leading to hypocalcemia, hyperphosphatemia, and a range of associated symptoms and complications.[2] Conventional management of hypoparathyroidism typically involves supplementation with calcium and active vitamin D analogues, which can be challenging to optimize and may lead to long-term complications such as hypercalciuria, nephrocalcinosis, and renal insufficiency.[7] While PTH peptide analogues (e.g., teriparatide, abaloparatide, palopegteriparatide) offer hormone replacement, they necessitate parenteral administration, which can be burdensome for patients requiring chronic therapy.[6] PCO-371 was therefore conceived as an orally administered agent that could potentially overcome the limitations of both conventional supplementation and injectable PTH therapies by providing a more convenient and physiological means of PTHR1 activation.[2]

The development of an orally active small molecule agonist for PTHR1, a Class B G protein-coupled receptor (GPCR), represents a considerable scientific challenge. Class B GPCRs are characterized by large, complex N-terminal extracellular domains that recognize endogenous peptide ligands, making it difficult for small molecules to effectively mimic these interactions at the orthosteric site or to identify suitable allosteric sites for modulation.[4] The progression of PCO-371 into Phase 1 clinical evaluation, despite these inherent difficulties, highlighted the significant unmet medical need in hypoparathyroidism and the innovative approach taken in its design.

1.2. Developer

PCO-371 was discovered and developed by Chugai Pharmaceutical Co., Ltd., a Japanese pharmaceutical company.[4] Examination of Chugai Pharmaceutical's publicly available pipeline disclosures and annual reports during the period of PCO-371's active development (circa 2015-2020) reveals a diminishing presence or eventual absence of the compound in later strategic updates.[20] Such a pattern in corporate communications often indicates an internal decision to deprioritize or discontinue a development program, particularly for early-stage assets, which aligns with the subsequent confirmed termination of PCO-371's clinical trials.

1.3. Intended Indication

The primary therapeutic indication targeted for PCO-371 was hypoparathyroidism.[2] This focus is underscored by the U.S. Food and Drug Administration (FDA) granting Orphan Drug Designation to PCO-371 for this condition.[4] While preclinical studies also explored its potential utility in osteoporosis, leveraging the known anabolic effects of PTHR1 activation on bone, the results with oral administration in animal models of osteopenia were less compelling than its effects on calcium homeostasis.[2] Consequently, the clinical development program appeared to prioritize hypoparathyroidism. The selection of a rare disease like hypoparathyroidism, along with obtaining Orphan Drug Designation, often reflects a strategic approach to address significant unmet medical needs in smaller, well-defined patient populations, where regulatory incentives might facilitate a more focused development pathway. However, the eventual discontinuation of PCO-371 suggests that the clinical data did not support a favorable risk-benefit profile, even with these strategic advantages.

1.4. Initial Promise and Novelty

PCO-371 was distinguished in early scientific reports as potentially the first orally active, non-peptide small-molecule PTHR1 agonist to demonstrate efficacy in animal models of hypoparathyroidism and osteoporosis, along with good oral bioavailability in rats.[6] A key aspect of its novelty lay in its unique mechanism of interaction with PTHR1. It was described as functioning as a "molecular wedge" by binding to a novel, allosteric site within the intracellular cavity of the receptor, thereby stabilizing the active conformation of PTHR1 in complex with its cognate Gs protein.[4] This represented a significant conceptual advance for targeting Class B GPCRs, which have historically been refractory to small molecule drug discovery efforts.

2. Chemical and Pharmaceutical Profile

2.1. Nomenclature and Identifiers

PCO-371 is identified by several names and codes across various databases and publications.

• Primary Name: PCO-371 (also commonly PCO371) [1]
• Synonyms: PC-0371 [1], compound 16c (referring to its designation in the Nishimura et al. 2020 publication) [1], CPD2050.[37]
• IUPAC Name: 1-[3,5-dimethyl-4-[[4-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-5,5-dimethylimidazolidine-2,4-dione.[2]
• CAS Number: 1613373-33-3.[1]
• DrugBank ID: DB14946.[1]
• FDA UNII: TE53TU0WSQ.[1]

2.2. Drug Type

PCO-371 is classified as a synthetic organic Small Molecule.[1] It is a non-peptide agonist of PTHR1.[6]

2.3. Physicochemical Properties

The structural and physicochemical characteristics of PCO-371 are summarized in Table 1. It is a complex organic molecule with multiple heterocyclic rings and functional groups contributing to its interaction with the target receptor and its pharmacokinetic properties.

Table 1: Chemical and Pharmaceutical Profile of PCO-371

Property	Value	Source(s)
IUPAC Name	1-[3,5-dimethyl-4-[[4-oxo-2-[4-(trifluoromethoxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]-5,5-dimethylimidazolidine-2,4-dione	2
CAS Number	1613373-33-3	1
DrugBank ID	DB14946	1
Molecular Formula	C29H32F3N5O6S	1
Molecular Weight	~635.66 g/mol (variations: 635.7, 635.659)	1
Drug Type	Small Molecule, Non-peptide	1
Key Synonyms	PCO371, PC-0371, compound 16c	1
Appearance	Solid powder, white to off-white	2
Solubility (Water)	0.00721 mg/mL (ALOGPS prediction)	1
Solubility (Organic)	Soluble in DMSO; Ethanol: 2 mg/mL	1
logP (predicted)	3.64 (ALOGPS), 3.81 (Chemaxon)	1
pKa (Strongest Acidic)	~8.39 - 8.59 (predicted)	1
pKa (Strongest Basic)	~2.53 (predicted)	1
Rule of Five Violation	Yes (primarily MW > 500, H-bond acceptors > 10)	1

The low predicted aqueous solubility of PCO-371 (0.00721 mg/mL [1]) is a notable characteristic that often presents challenges for oral drug formulation and absorption. While PCO-371 was developed as an orally active agent and demonstrated efficacy via this route in preclinical models (often with enabling formulations such as those containing DMSO, PEG300, Tween-80, or SBE-β-CD [16]), this inherent low solubility could have contributed to variability in human pharmacokinetics or required sophisticated formulation strategies, potentially impacting the overall risk-benefit assessment during clinical trials. Furthermore, PCO-371 violates certain aspects of Lipinski's Rule of Five, particularly regarding molecular weight and hydrogen bond acceptor count.[1] While these rules are guidelines and not absolute determinants of oral bioavailability, such deviations can flag potential issues with absorption or permeability. Nevertheless, its progression to oral human trials indicates that sufficient systemic exposure was achievable, at least initially.

3. Pharmacology

3.1. Mechanism of Action

PCO-371 functions as a potent, selective, and orally active full agonist of the human parathyroid hormone receptor type 1 (hPTHR1).[1] PTHR1 is a Class B GPCR crucial for calcium and phosphate homeostasis and bone metabolism.[6] PCO-371 exhibits high selectivity for PTHR1 over the PTH type 2 receptor (PTHR2), with an EC50​ for PTHR2 activation greater than 100 μM.[3]

A distinguishing feature of PCO-371 is its novel binding site and mode of action. Unlike endogenous peptide ligands (PTH and PTH-related peptide) which bind to the extracellular domain and transmembrane helices of PTHR1, PCO-371 interacts with an allosteric binding pocket located at the cytoplasmic interface of PTHR1 and its cognate Gs protein.[17] This intracellular pocket involves transmembrane segments TM2, TM3, TM6, and TM7, as well as intracellular helix 8. PCO-371 is described as acting as a "molecular wedge," inserting into this site to stabilize the active conformation of the receptor in complex with Gs.[4] The interaction is critically dependent on Proline 415 (P415^6.47b) in TM6 of hPTHR1, which contributes to both receptor activation and selectivity over PTHR2.[6]

Furthermore, PCO-371 is characterized as a G protein-biased agonist. It preferentially activates Gs protein-mediated signaling pathways, leading to cyclic AMP (cAMP) production, over β-arrestin recruitment and its associated signaling cascades.[4] This biased agonism was a deliberate design strategy, potentially aiming to enhance therapeutic efficacy while minimizing adverse effects or receptor desensitization that can be associated with β-arrestin pathways. The discovery of this unique intracellular binding site and the Gs-biased agonism of PCO-371 offered a novel approach to modulating Class B GPCRs, which have traditionally been difficult targets for small-molecule drugs.

3.2. Pharmacodynamics

In Vitro Effects:

PCO-371 demonstrated potent agonistic activity at hPTHR1 in cellular assays. It stimulated cAMP production in COS-7 cells expressing hPTHR1 with an EC50​ of 2.4 μM, and a similar potency (EC50​ = 2.5 μM) was observed in cells expressing an N-terminally truncated hPTHR1 (hPTHR1-delNT), supporting its interaction with the transmembrane domain.3 PCO-371 also enhanced phospholipase C (PLC) activity, albeit with a higher EC50​ of 17 μM.3 Competition binding assays showed that PCO-371 could displace a radiolabeled peptide known to bind the transmembrane domain of PTHR1, further confirming its interaction site.6

Ex Vivo Effects:

In isolated fetal rat long bones, PCO-371 (at 1 and 3 μM) induced calcium release, an effect characteristic of PTHR1 activation.6

In Vivo Effects (Animal Models):

• Hypoparathyroidism Model (Thyroparathyroidectomized - TPTX rats): Oral administration of PCO-371 dose-dependently increased serum calcium and decreased serum phosphate levels. Crucially, it achieved this normalization of serum calcium (target range 7.6–11.2 mg dl^-1) without a concomitant increase in urinary calcium excretion, even with repeated dosing (up to 9 mg/kg for 4 weeks). This suggests that PCO-371 effectively stimulated renal calcium reabsorption, a key physiological action of PTH. The effects of PCO-371 on serum calcium were reported to be stronger and more prolonged compared to subcutaneous injections of hPTH(1–34) or hPTH(1–84).[2] Treatment with PCO-371 also led to a significant increase in serum 1α,25-dihydroxyvitamin D3 levels.[28]
• Osteopenia Model (Ovariectomized - OVX rats): Daily oral administration of PCO-371 (e.g., 30 mg/kg) increased bone turnover markers, including serum osteocalcin and urinary C-terminal telopeptide of type I collagen (CTX)/creatinine. However, its effect on significantly increasing bone mineral density (BMD) or bone strength was limited when given orally, with only partial increases observed in the proximal femur and no significant effects on lumbar spine BMD. In contrast, intravenous administration of PCO-371 (10 mg/kg/day) or subcutaneous hPTH(1–34) injections resulted in significant increases in BMD and bone strength in the lumbar vertebrae of OVX rats.[2]

The preclinical pharmacodynamic profile of PCO-371 was particularly promising for hypoparathyroidism, where the ability to normalize serum calcium without inducing hypercalciuria addressed a significant limitation of conventional therapies. The observed discrepancy in bone anabolic effects between oral and intravenous PCO-371 in osteopenic rats likely reflects challenges in achieving the necessary pharmacokinetic profile (e.g., sustained high exposure or specific pulsatility at the bone tissue) with oral administration for robust bone formation, as opposed to the more readily achieved modulation of calcium homeostasis. This difference probably influenced the primary clinical development focus towards hypoparathyroidism.

3.3. Pharmacokinetics

Animal Pharmacokinetics:

PCO-371 demonstrated oral bioavailability in rats. For instance, at an oral dose of 2 mg/kg in normal rats, the bioavailability was reported as 34%. The serum half-life (T1/2​) was approximately 1.5 hours, and the time to maximum concentration (Tmax​) was also around 1.5 hours.6 In TPTX rats, PCO-371 exhibited a longer serum half-life and Tmax​ compared to hPTH(1–84), contributing to its more sustained pharmacodynamic effects.6

Human Pharmacokinetics:

Human pharmacokinetic data were planned to be generated from several Phase 1 studies:

• NCT02475616: A single ascending dose study in healthy volunteers, which was terminated, aimed to evaluate PK.[5]
• NCT04649216: This Phase 1 study in healthy male volunteers was designed to investigate the excretion balance, pharmacokinetics, and metabolism of a single oral dose of [14C]PCO371, as well as the PK of an intravenous tracer dose of [14C]PCO371 to determine absolute oral bioavailability.[5] This study was reported as completed.[5] However, specific results from this study were not publicly detailed in the provided information, cited due to commercial sensitivity.[19]
• NCT04209179: A study in patients with hypoparathyroidism, which was also terminated, included PK evaluation as an objective.[5]

The completion of the human mass balance and metabolism study (NCT04649216) is a standard and critical step in early drug development. The data from this study would have provided essential information regarding the absorption, distribution, metabolism, and excretion (ADME) properties of PCO-371 in humans, which is vital for guiding further clinical development, including dose selection for patient trials. The unavailability of these detailed human PK results in the public domain, combined with the termination of other clinical trials, makes a full assessment of its human PK profile challenging.

4. Preclinical Development

4.1. In Vitro and Ex Vivo Efficacy

As detailed in the Pharmacology section (3.2), PCO-371 demonstrated potent and selective agonism at hPTHR1 in various in vitro cell-based assays, stimulating both cAMP production (EC50 ≈ 2.4-2.5 μM) and PLC activity (EC50 ≈ 17 μM).[3] It also induced calcium release from fetal rat long bones ex vivo.[6]

4.2. In Vivo Efficacy

The in vivo efficacy of PCO-371 was primarily assessed in rat models of hypoparathyroidism (TPTX rats) and osteopenia (OVX rats), as described under Pharmacodynamics (3.2). In TPTX rats, oral PCO-371 effectively normalized serum calcium and phosphate levels without causing hypercalciuria, demonstrating a superior profile to PTH injections in terms of duration of action and urinary calcium effects.[2] In OVX rats, while PCO-371 increased bone turnover markers, its oral administration had a limited impact on BMD compared to intravenous administration, which showed effects comparable to PTH.[2]

4.3. Lead Optimization and Avoidance of Reactive Metabolites

A critical aspect of PCO-371's preclinical development was the optimization of a lead compound, CH5447240 (identified as compound 1 in Nishimura et al., 2020), which was found to form a reactive metabolite.[24]

• Reactive Metabolite Issue with Precursor: CH5447240 underwent metabolic activation in human liver microsome assays, leading to the formation of a putative iminoquinone (compound 19), which was subsequently trapped as a glutathione (GSH) adduct (compound 20).[27] Such reactive metabolites are a significant safety concern in drug development due to their potential to covalently bind to cellular macromolecules, leading to idiosyncratic drug toxicity, including hepatotoxicity.[40]
• Structural Modifications to PCO-371: PCO-371 (compound 16c in Nishimura et al., 2020) was derived from CH5447240 through extensive structure-activity relationship (SAR) studies. Key modifications included replacing the N-methylurea moiety of the lead compound with a hydantoin ring and altering the p-phenethylsulfonamide portion. These changes were specifically designed to circumvent the metabolic pathway leading to the reactive iminoquinone while maintaining or enhancing PTHR1 agonistic activity and improving metabolic stability.[24]
• Successful Mitigation: PCO-371 successfully tested negative for GSH-adduct formation in human liver microsome assays, indicating that the structural modifications effectively eliminated the formation of the problematic reactive metabolite.[27] This achievement was a crucial de-risking step, suggesting an improved intrinsic safety profile for PCO-371 concerning this specific metabolic liability and enabling its progression into clinical trials.

4.4. Preclinical Safety and Toxicology

General statements from early publications indicated a favorable preclinical safety profile for PCO-371. The Tamura et al. (2016) study in Nature Communications reported that "no serious side effects of PCO371 were observed in preclinical toxicology studies".[6] The successful mitigation of the reactive metabolite issue, as detailed by Nishimura et al. (2020), further supported a potentially improved safety profile for PCO-371 compared to its precursors.[24]

However, a theoretical class-based concern for PTHR1 agonists is the potential risk of osteosarcoma, which has been observed in rat carcinogenicity studies with supra-therapeutic doses of PTH peptide analogs. While Tamura et al. acknowledged this risk, they posited that the bone formation profile of orally administered PCO-371 might differ from that of injectable PTH peptides, potentially mitigating this concern.[6] Nevertheless, this would have remained an area of long-term safety monitoring had development progressed further. The progression of PCO-371 to Phase 1 human trials implies that the initial preclinical safety and toxicology data package was deemed acceptable by regulatory authorities.

5. Clinical Development Program

PCO-371 advanced into Phase 1 clinical trials, investigating its safety, tolerability, pharmacokinetics, and pharmacodynamics in both healthy volunteers and patients with hypoparathyroidism. However, the clinical development program was ultimately discontinued.

5.1. Overview of Clinical Trials

Table 2 summarizes the key Phase 1 clinical trials conducted for PCO-371.

Table 2: Summary of PCO-371 Clinical Trials

NCT ID	Phase	Title	Sponsor	Population	Status	Key Objectives/Reason for Termination (if specified)
NCT02475616	1	A Single Ascending Dose Study of PCO371 in Healthy Volunteers 4	Chugai Pharmaceutical 5	Healthy Volunteers (Caucasian and Japanese) 5	Terminated/ Discontinued (Nov 2015) 4	Evaluate safety, tolerability, PK of single ascending oral doses.5 Reason for termination not specified for this trial directly, but part of overall program discontinuation.
NCT04649216	1	A Phase I, Single-Center, Open-Label Study Investigating the Excretion Balance, Pharmacokinetics (PK) and Metabolism of a Single Oral Dose of [14C]PCO371 and PK of an Intravenous (IV) Tracer of [14C]PCO371 in Healthy Male Subjects 5	Chugai Pharmaceutical 5	Healthy Male Volunteers 19	Completed 5	Assess excretion balance, PK, metabolism, absolute oral bioavailability.19 No lay summary of results provided due to commercial sensitivity.19
NCT04209179 (JapicCTI-194970)	1	A Clinical Study Investigating the Safety, Tolerability, PK and PD of PCO371 in Patients With Hypoparathyroidism 5	Chugai Pharmaceutical 5	Patients with Hypoparathyroidism 5	Terminated 15	Evaluate safety, tolerability, PK, and PD in patients. Terminated due to "uncertain risk-benefit balance, not further specified".15

This table provides a consolidated view of the clinical trials undertaken for PCO-371. It is valuable as it clearly outlines the scope of human investigation, the populations studied, and, critically, the status and reasons for termination of these studies, which are central to understanding the drug's development trajectory and eventual discontinuation.

5.2. NCT02475616: Single Ascending Dose Study in Healthy Volunteers

This initial Phase 1 study was designed as a single-center, placebo-controlled, randomized, double-blind, dose-escalation trial. It aimed to evaluate the safety, tolerability, and pharmacokinetics of single ascending oral doses of PCO-371 in healthy Caucasian and Japanese subjects.[5] The trial was initiated in June 2015 but was subsequently terminated or discontinued in November 2015.[4] The specific reasons for the termination of this particular trial are not explicitly detailed in the provided information, but it marked an early setback in the clinical program. The termination of a first-in-human, single ascending dose study often suggests that adverse safety or tolerability signals were observed at early dose levels, or that the pharmacokinetic profile was highly unfavorable, precluding further dose escalation or progression to multiple-dose studies.

5.3. NCT04649216: Excretion Balance, PK, and Metabolism Study in Healthy Volunteers

This Phase 1, single-center, open-label study was conducted in healthy male subjects to investigate the excretion balance, pharmacokinetics, and metabolism of a single oral dose of radiolabeled [14C]PCO371. It also aimed to determine the pharmacokinetics of an intravenous (IV) tracer dose of [14C]PCO371, which would allow for the calculation of absolute oral bioavailability.[5] This study, initiated in November 2020, was reported as completed.[5] However, a lay summary of the results was not provided, with the sponsor citing the Phase 1 nature of the study in healthy volunteers and commercial sensitivity as reasons.[19] The completion of this human ADME (Absorption, Distribution, Metabolism, Excretion) study is a standard component of early clinical development, providing critical data on how the drug is processed by the human body. The timing of this study's completion relative to the termination of other PCO-371 trials is noteworthy. If this study was completed after the decision to halt other parts of the program, its purpose might have been to gather comprehensive data for regulatory closure or to fully understand the drug's disposition in light of issues observed in other trials.

5.4. NCT04209179 (JapicCTI-194970): Study in Patients With Hypoparathyroidism

This Phase 1 trial was a randomized, double-blind, multiple ascending oral dose study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PCO-371 specifically in patients with hypoparathyroidism.[5] The study was initiated in July 2020 but was subsequently terminated.[15] The explicitly stated reason for the termination of this patient trial was an "uncertain risk-benefit balance, not further specified".[15] This indicates that in the target patient population, the observed therapeutic effects did not sufficiently outweigh the perceived risks, or that unacceptable safety or tolerability issues emerged.

5.5. Overall Clinical Safety and Tolerability Profile

Detailed clinical safety and tolerability data for PCO-371 are limited in the public domain due to the early termination of key trials and the lack of published results. The termination of the initial SAD study (NCT02475616) in healthy volunteers hints at potential early safety, tolerability, or significant PK issues.[4] The subsequent termination of the patient study (NCT04209179) due to an "uncertain risk-benefit balance" [15] further reinforces that the clinical profile observed was not favorable for continued development.

6. Regulatory Status and Discontinuation of Development

6.1. Orphan Drug Designation

PCO-371 received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of hypoparathyroidism.[5] This designation is granted to drugs intended for rare diseases (affecting fewer than 200,000 people in the U.S.) and provides incentives to sponsors, such as market exclusivity and tax credits, to encourage the development of treatments for such conditions. The FDA Orphan Drug designation number 455914 is associated with PCO-371 for this indication.[5] There is no information in the provided snippets to suggest that PCO-371 received a similar designation from the European Medicines Agency (EMA); other PTH analogs have received EMA orphan designation for hypoparathyroidism.[42] The FDA designation highlighted the recognized unmet medical need for new hypoparathyroidism treatments and would have offered developmental advantages to Chugai Pharmaceutical.

6.2. Analysis of Development Discontinuation

The clinical development of PCO-371 was definitively discontinued by Chugai Pharmaceutical.[4]

• The single ascending dose study in healthy volunteers (NCT02475616) was terminated in November 2015.[4]
• The multiple ascending dose study in patients with hypoparathyroidism (NCT04209179) was terminated due to an "uncertain risk-benefit balance," with no further specification provided in the available sources.[15]
• Multiple drug development databases, including AdisInsight, DrugHunter, and Synapse by Patsnap, corroborate the discontinued status of PCO-371, typically listing its highest development phase as "Discontinued Phase 1".[4]
• No recent reports of active development for PCO-371 have been identified since these terminations [5], and the compound is not featured in Chugai's recent pipeline disclosures.[20]

The consistent reporting of trial terminations across multiple platforms, particularly the explicit reason of "uncertain risk-benefit balance" for the patient trial NCT04209179 [15], points to a definitive decision by Chugai Pharmaceutical to halt the PCO-371 program. This decision was likely based on an unfavorable assessment of the drug's performance in early human studies, where the potential benefits observed did not adequately outweigh the identified or potential risks. This could have stemmed from insufficient efficacy at tolerable doses, the emergence of unacceptable adverse events in healthy volunteers or patients, or a combination of these factors.

7. Discussion and Conclusion

7.1. Summary of PCO-371's Profile and Development Journey

PCO-371 emerged from a dedicated medicinal chemistry effort by Chugai Pharmaceutical as an orally bioavailable, non-peptide small-molecule agonist of PTHR1. Its novel mechanism, involving Gs-biased agonism via a unique intracellular binding site, represented a sophisticated approach to modulating a Class B GPCR. Preclinical studies were promising, particularly for the treatment of hypoparathyroidism, where PCO-371 demonstrated the ability to normalize serum calcium without inducing hypercalciuria in animal models. A significant preclinical hurdle, the formation of a reactive metabolite by a lead compound, was successfully overcome in the design of PCO-371.

Despite this promising preclinical profile and achieving FDA Orphan Drug Designation for hypoparathyroidism, the clinical development program encountered insurmountable challenges. Phase 1 studies, including an initial single ascending dose trial in healthy volunteers (NCT02475616) and a subsequent trial in patients with hypoparathyroidism (NCT04209179), were terminated. The most explicitly stated reason for the patient trial termination was an "uncertain risk-benefit balance." While a human ADME study (NCT04649216) was completed, its results were not publicly detailed, and the overall program was discontinued.

7.2. Challenges in Developing Oral Small Molecule PTHR1 Agonists

The development of PCO-371 highlights the substantial challenges inherent in creating orally active small-molecule modulators for Class B GPCRs, such as PTHR1. These receptors have evolved to bind large peptide hormones, and their orthosteric sites are often not amenable to high-affinity, selective interaction with small molecules.4 Identifying allosteric sites, as was done for PCO-371, is a complex endeavor.

Key challenges include:

• Achieving Potency and Selectivity: Designing small molecules that can effectively activate these receptors with sufficient potency and selectivity over related receptors (like PTHR2) is difficult.
• Oral Bioavailability and Pharmacokinetics: Ensuring adequate oral absorption, favorable metabolic stability, and an appropriate pharmacokinetic profile for the intended dosing regimen (often chronic for conditions like hypoparathyroidism) is a major hurdle, especially for molecules that may deviate from ideal physicochemical properties.[12]
• Translating Preclinical Efficacy: Positive results in animal models do not always translate to human efficacy, particularly for complex endocrine regulation.
• Safety and Tolerability: Balancing on-target pharmacodynamic effects (e.g., changes in calcium levels) with potential on-target (e.g., hypercalcemia, long-term bone effects) and off-target adverse events is critical. The need for chronic administration in hypoparathyroidism places a high bar on the long-term safety profile. The field continues to pursue oral small molecule PTH1R agonists, as evidenced by ongoing efforts from other companies like Septerna with candidates such as SP-1462 [10], underscoring the persistent unmet medical need.

7.3. Concluding Remarks on the PCO-371 Program

The PCO-371 development program, while ultimately unsuccessful in delivering a new therapeutic, represents a scientifically valuable endeavor. It demonstrated that innovative medicinal chemistry approaches could yield orally active small-molecule agonists for the challenging PTHR1 target, even addressing significant preclinical liabilities such as reactive metabolite formation. The identification of a novel allosteric binding site and the characterization of a G-protein biased agonist contribute important knowledge to the field of GPCR pharmacology.

The discontinuation of PCO-371 due to an "uncertain risk-benefit balance" in early clinical trials underscores the high attrition rate in pharmaceutical R&D, particularly when translating novel mechanisms and complex pharmacology from preclinical models to human patients. While the precise details leading to this conclusion are not fully public, the PCO-371 story serves as a salient reminder of the rigorous safety and efficacy standards that investigational drugs must meet. The insights gained from its development may yet inform future efforts to create improved therapies for hypoparathyroidism and other disorders involving Class B GPCRs.

8. References

(A comprehensive list of references corresponding to the cited snippets [1] would be compiled here in a full report, linking to the original publications or database entries.)

• Nishimura Y, Esaki T, Isshiki Y, Furuta Y, Mizutani A, Kotake T, Emura T, Watanabe Y, Ohta M, Nakagawa T, Ogawa K, Arai S, Noda H, Kitamura H, Shimizu M, Tamura T, Sato H. Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist. J Med Chem. 2020;63(10):5089-5099. [17]
• Tamura T, Noda H, Joyashiki E, Hoshino M, Watanabe T, Kinosaki M, Nishimura Y, Esaki T, Ogawa K, Miyake T, Arai S, Shimizu M, Kitamura H, Sato H, Kawabe Y. Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism. Nat Commun. 2016 Nov 18;7:13384. [6]
• DrugBank: PCO-371 (DB14946). [1]
• PubChem: PCO-371 (CID 76283707 - note potential discrepancy, cross-reference with CAS). [29]
• ClinicalTrials.gov: NCT02475616, NCT04649216, NCT04209179. [4]
• Other database entries and articles as cited by snippet IDs throughout the report.

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