Journal of medicinal chemistry · 2020
Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist.
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Nishimura Yoshikazu, Esaki Toru, Isshiki Yoshiaki, Furuta Yoshiyuki, Mizutani Akemi, Kotake Tomoya, Emura Takashi, Watanabe Yoshiaki, Ohta Masateru, Nakagawa Toshito, Ogawa Kotaro, Arai Shinichi, Noda Hiroshi, Kitamura Hidetomo, Shimizu Masaru, Tamura Tatsuya, Sato Haruhiko
Аннотация
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.