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Novel pyrrolidine melanin-concentrating hormone receptor 1 antagonists with reduced hERG inhibition.

Abstract：

:We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Fox BM,Natero R,Richard K,Connors R,Roveto PM,Beckmann H,Haller K,Golde J,Xiao SH,Kayser F

doi

10.1016/j.bmcl.2011.02.046

subject

Has Abstract

pub_date

2011-04-15 00:00:00

pages

2460-7

issue

8

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(11)00230-7

journal_volume

21

pub_type

杂志文章

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