Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist
dataset
posted on 2020-02-17, 14:12 authored by Yoshikazu Nishimura, Toru Esaki, Yoshiaki Isshiki, Yoshiyuki Furuta, Akemi Mizutani, Tomoya Kotake, Takashi Emura, Yoshiaki Watanabe, Masateru Ohta, Toshito Nakagawa, Kotaro Ogawa, Shinichi Arai, Hiroshi Noda, Hidetomo Kitamura, Masaru Shimizu, Tatsuya Tamura, Haruhiko SatoWe 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.
