Synthesis and SAR Investigations for Novel Melanin-Concentrating Hormone 1 Receptor (MCH1) Antagonists Part 1. The Discovery of Arylacetamides as Viable Replacements for the Dihydropyrimidi

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• 作者：Yu Jiang ; Chien-An Chen ; Kai Lu ; Irena Daniewska ; John De Leon ; Ron Kong ; Carlos Forray ; Boshan Li ; Laxminarayan G. Hegde ; Toni D. Wolinsky ; Douglas A. Craig ; John M. Wetzel ; Kim Andersen ; Mohammad R.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 9, 2007
• 年：2007
• 卷：50
• 期：16
• 页码：3870 - 3882
• 全文大小：207K
• 年卷期：v.50,no.16(August 9, 2007)
• ISSN：1520-4804

文摘

Melanin-concentrating hormone (MCH) is involved in the regulation of feeding, water balance, energymetabolism, general arousal and attention state, memory, cognitive functions, and psychiatric disorders.Herein, two new chemical series exemplified by N-[5-(1-{3-[2,2-bis-(4-fluoro-phenyl)-acetylamino]-propyl}-piperidin-4-yl)-2,4-difluoro-phenyl]-isobutyramide (SNAP 102739, 5m) and N-[3-(1-{3-[(S)-2-(4-fluoro-phenyl)-propionylamino]-propyl}-piperidin-4-yl)-4-methylphenyl]-isobutyramide ((S)-6b) are reported. Thesecompounds were designed to improve the pharmacokinetic properties of the high-throughput screening leadcompound 1 (SNAP 7941). The MCH₁ receptor antagonists 5m and (S)-6b show reasonable pharmacokineticprofiles (rat bioavailability = 48 and 81%, respectively). Compounds 5m and (S)-6b demonstrated theinhibition of a centrally administered MCH-evoked drinking effect, and compound 5m exhibited oral invivo efficacy in the rat social interaction model of anxiety, with a minimum effective dose = 0.3 mg/kg.