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

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.