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Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity.

Abstract：

:Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Smith RA,Fathi Z,Achebe F,Akuche C,Brown SE,Choi S,Fan J,Jenkins S,Kluender HC,Konkar A,Lavoie R,Mays R,Natoli J,O'Connor SJ,Ortiz AA,Su N,Taing C,Tomlinson S,Tritto T,Wang G,Wirtz SN,Wong W,Yang XF,Ying S,

doi

10.1016/j.bmcl.2007.03.011

subject

Has Abstract

pub_date

2007-05-15 00:00:00

pages

2706-11

issue

10

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(07)00297-1

journal_volume

17

pub_type

杂志文章

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