MCH is expressed predominantly in the lateral hypothalamus of the brain and is known to be involved in both regulation of feeding and energy homeostasis. The effects of MCH are mediated by G protein-coupled receptor, MCH receptor-1 (MCH-R1). The results of previous genetic and pharmacological studies demonstrated that MCH-R1 plays an important role in the control food intake and body-weight and suggested that this receptor is one of the most promising targets for the obesity treatment. As part of a continuing drug discovery program aimed at the development of potent MCH-R1 antagonists, we found that a novel series of 4-arylphthalazin-1(2H)-one linked to arylpiperidines display highly potent binding affinities to MCH-R1.The results of an extensive SAR study probing the effects of substituents on the 4-arylphthalazin-1(2H)-one C-4 aryl group led to the identification of the 4-(3,4-difluorophenyl) derivative as a highly potent MCH-R1 inhibitor with an IC50 = 1 nM.

4-Arylphthalazin-1(2H)-one derivatives as potent antagonists of the melanin concentrating hormone receptor 1 (MCH-R1)

244th National Meeting (2012)

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