Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the mel...
Basic Information
ID: ALA1138325
Journal: J Med Chem
Title: Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor.
Authors: Tran JA, Jiang W, Tucci FC, Fleck BA, Wen J, Sai Y, Madan A, Chen TK, Markison S, Foster AC, Hoare SR, Marks D, Harman J, Chen CW, Arellano M, Marinkovic D, Bozigian H, Saunders J, Chen C.
Abstract: Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
CiteXplore: 17994683
DOI: 10.1021/jm701137s
Patent ID: ┄