PCO371
[CAS# 1613373-33-3]

Identification

• Classification: Biochemical >> Inhibitor >> Endocrinology & hormones
• Name: PCO371
• Synonyms: 1-[3,5-dimethyl-4-[2-[[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
• Molecular Formula: C₂₉H₃₂F₃N₅O₆S
• Molecular Weight: 635.65
• CAS Registry Number: 1613373-33-3
• SMILES: CC1=CC(=CC(=C1CCS(=O)(=O)N2CCC3(CC2)C(=O)NC(=N3)C4=CC=C(C=C4)OC(F)(F)F)C)N5C(=O)NC(=O)C5(C)C

Properties

• Density: 1.5±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.636, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P321-P332+P313-P337+P313-P362-P403+P233-P405-P501

Discovery and Applications

PCO371 is a small-molecule agonist specifically targeting the parathyroid hormone receptor 1 (PTH1R), a G protein-coupled receptor involved in regulating calcium homeostasis and bone metabolism. The compound was discovered through structure-based drug design and high-throughput screening efforts aimed at developing orally available agents that could mimic the activity of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP).

PCO371 activates PTH1R by binding to its transmembrane domain, inducing receptor conformational changes that stimulate downstream signaling pathways, including cyclic AMP (cAMP) production and phospholipase C activation. This mode of action promotes anabolic effects on bone, such as increased osteoblast activity and bone formation, making PCO371 a promising candidate for treating conditions characterized by low bone density, such as osteoporosis.

The compound’s development addresses limitations associated with peptide-based therapies targeting PTH1R, which typically require injection and have limited stability. PCO371’s oral bioavailability offers a significant advantage for patient compliance and long-term treatment.

Preclinical studies have demonstrated that PCO371 effectively stimulates bone formation and increases bone mineral density in animal models. Its selective mechanism reduces the risk of hypercalcemia compared to non-selective agonists. Clinical trials are underway to evaluate the safety, pharmacokinetics, and efficacy of PCO371 in patients with osteoporosis and other metabolic bone diseases.

Beyond bone-related applications, research is ongoing to explore the potential effects of PCO371 on kidney function and mineral metabolism due to PTH1R’s role in these physiological processes.

In summary, PCO371 is a selective, orally available PTH1R agonist designed to stimulate bone formation and improve bone health. Its discovery marks progress in developing small-molecule therapeutics for metabolic bone disorders, offering potential benefits over existing peptide treatments.

References

2016. Identification of an orally active small-molecule PTHR1 agonist for the treatment of hypoparathyroidism. Nature Communications, 7.
DOI: 10.1038/ncomms13384

2020. Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist. Journal of Medicinal Chemistry, 63(3).
DOI: 10.1021/acs.jmedchem.9b01743

2023. TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Research, 52(D1).
DOI: 10.1093/nar/gkad751