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
  • 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.