当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Design, synthesis, and biological evaluation of substituted 2-cyclohexyl-4-phenyl-1H-imidazoles: potent and selective neuropeptide Y Y5-receptor antagonists.

Design, synthesis, and biological evaluation of substituted 2-cyclohexyl-4-phenyl-1H-imidazoles: potent and selective neuropeptide Y Y5-receptor antagonists.

Abstract：

:Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series of small molecule Y5 antagonists derived from a 2,4-diaryl-1H-imidazole lead. The main objectives of our structural optimization efforts were to produce novel and potent Y5 antagonists with an improved oral pharmacokinetic profile and less affinity for the hERG potassium channel compared to the lead 2,4-diarylimidazole structures. These goals were accomplished by replacement of the 2-aryl ring with a cyclohexyl ring and subsequent elaboration of the 4-position of the cyclohexyl ring with a variety of hydrophilic functionalities. The resulting compound, N-(2-hydroxy-tert-butyl)(4-[4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]cyclohexyl)carboxamide (20), displayed good potency at the Y5 receptor (K(i) = 3 nM), while interactions at the hERG channel were essentially eliminated (6% inhibition at a concentration of 3 microM). Importantly, the pharmacokinetic properties of 20 (F = 36%) represented a marked improvement over that of the initial 2,4-diarylimidazole structures.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Blum CA,Zheng X,De Lombaert S

doi

10.1021/jm030490g

keywords:

subject

Has Abstract

pub_date

2004-04-22 00:00:00

pages

2318-25

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

47

pub_type

杂志文章

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