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Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Nishimura Y,Esaki T,Isshiki Y,Furuta Y,Mizutani A,Kotake T,Emura T,Watanabe Y,Ohta M,Nakagawa T,Ogawa K,Arai S,Noda H,Kitamura H,Shimizu M,Tamura T,Sato H

doi

10.1021/acs.jmedchem.9b01743

subject

Has Abstract

pub_date

2020-05-28 00:00:00

pages

5089-5099

issue

10

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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