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 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;
Journal Journal of medicinal chemistry
Year 2020
DOI
10.1021/acs.jmedchem.9b01743
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