PCO371 / Roche - LARVOL DELTA

Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety. (PubMed, ChemMedChem) - "We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose-dependently induces PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats...As results of the initial derivatization of 2a, we identified the indole derivatives as another scaffold. In this article, we report on the structure-activity relationship (SAR), structure-metabolism relationship (SMR), and structure-solubility relationship (SSR) of bicyclic aromatic derivatives, and the in vivo efficacy of 2j."

Journal • Osteoporosis • Rheumatology

Conserved class B GPCR activation by a biased intracellular agonist. (PubMed, Nature) - "Here we report the high-resolution structure of the human PTH1R in complex with the stimulatory G protein (G) and a small molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G. The binding site of PCO371 is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs...Together, these results uncover a distinct binding site for designing small molecule agonists for PTH1R and possible other members of class B GPCRs and define a receptor conformation that is only specific for G protein activation but not arrestin signaling. These insights should facilitate the design of distinct types of class B GPCR small molecule agonists for various therapeutic indications."

Journal • PTH2R

Class B1 GPCR activation by an intracellular agonist. (PubMed, Nature) - "Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor-transducer interface."

Journal

A Clinical Study Investigating the Safety, Tolerability, PK and PD of PCO371 in Patients With Hypoparathyroidism (clinicaltrials.gov) - P1; N=5; Terminated; Sponsor: Chugai Pharmaceutical; N=24 ➔ 5; Suspended ➔ Terminated; Trial primary completion date: May 2021 ➔ Dec 2020; Terminated on the basis of the currently uncertain risk-benefit balance for the patients, and the strategic position of the development program

Enrollment change • Trial primary completion date • Trial termination • Endocrine Disorders • Hypoparathyroidism • Renal Disease

Excretion Balance, PK and Metabolism of a Single Oral Dose of [14C]PCO371 (clinicaltrials.gov) - P1; N=11; Completed; Sponsor: Chugai Pharmaceutical; Active, not recruiting ➔ Completed

Clinical • Trial completion

Excretion Balance, PK and Metabolism of a Single Oral Dose of [14C]PCO371 (clinicaltrials.gov) - P1; N=12; Active, not recruiting; Sponsor: Chugai Pharmaceutical; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Clinical Study Investigating the Safety, Tolerability, PK and PD of PCO371 in Patients With Hypoparathyroidism (clinicaltrials.gov) - P1; N=24; Suspended; Sponsor: Chugai Pharmaceutical; Recruiting ➔ Suspended

Clinical • Trial suspension • Endocrine Disorders • Hypoparathyroidism • Renal Disease

Excretion Balance, PK and Metabolism of a Single Oral Dose of [14C]PCO371 (clinicaltrials.gov) - P1; N=12; Recruiting; Sponsor: Chugai Pharmaceutical

Clinical • New P1 trial

Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist. (PubMed, J Med Chem) - "In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 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 (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism."

Journal • Endocrine Disorders • Hypoparathyroidism • Renal Disease

A Clinical Study Investigating the Safety, Tolerability, PK and PD of PCO371 in Patients With Hypoparathyroidism (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Chugai Pharmaceutical; Not yet recruiting ➔ Recruiting; Initiation date: Jan 2020 ➔ May 2020

Clinical • Enrollment open • Trial initiation date • Endocrine Disorders • Hypoparathyroidism • Renal Disease

A Clinical Study Investigating the Safety, Tolerability, PK and PD of PCO371 in Patients With Hypoparathyroidism (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: Chugai Pharmaceutical

Clinical • New P1 trial