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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ID: 92795
2020
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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.
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nishimura2020leadjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors 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 Sato
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Journal Journal of medicinal chemistry
Year 2020
DOI
10.1021/acs.jmedchem.9b01743
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