2. Academic Validation
  3. Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist

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 May 28;63(10):5089-5099. doi: 10.1021/acs.jmedchem.9b01743.
Yoshikazu Nishimura 1,  Toru Esaki 1,  Yoshiaki Isshiki 1,  Yoshiyuki Furuta 1,  Akemi Mizutani 1,  Tomoya Kotake 1,  Takashi Emura 1,  Yoshiaki Watanabe 1,  Masateru Ohta 1,  Toshito Nakagawa 1,  Kotaro Ogawa 1,  Shinichi Arai 1,  Hiroshi Noda 1,  Hidetomo Kitamura 1,  Masaru Shimizu 1,  Tatsuya Tamura 1,  Haruhiko Sato 1
Affiliations

Affiliation

  • 1 Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
PMID: 32022560 DOI: 10.1021/acs.jmedchem.9b01743
Abstract

We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. 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.

Figures