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Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.

Abstract：

:An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Mihalic JT,Fan P,Chen X,Chen X,Fu Y,Motani A,Liang L,Lindstrom M,Tang L,Chen JL,Jaen J,Dai K,Li L

doi

10.1016/j.bmcl.2012.04.006

subject

Has Abstract

pub_date

2012-06-01 00:00:00

pages

3781-5

issue

11

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(12)00445-3

journal_volume

22

pub_type

杂志文章

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