Chen Chien-An, Jiang Yu, Lu Kai, Daniewska Irena, Mazza Christine G, Negron Leonardo, Forray Carlos, Parola Tony, Li Boshan, Hegde Laxminarayan G, Wolinsky Toni D, Craig Douglas A, Kong Ron, Wetzel John M, Andersen Kim, Marzabadi Mohammad R
Departments of Chemistry, Cellular Science and Target Discovery and Assessment, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652-1413, USA.
J Med Chem. 2007 Aug 9;50(16):3883-90. doi: 10.1021/jm060383x.
A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.
描述了一系列新型的黑色素浓缩激素（MCH1）受体拮抗剂，这些拮抗剂是通过将高通量筛选（HTS）命中化合物2（SNAP 7941）和化合物5（氯氟哌啶醇）的关键片段组合而成。以化合物11a - 11h、15a - 15h和16a - 16g为例的所得类似物，在体外和体内试验中评估了它们治疗情绪障碍的潜力。通过进一步的构效关系（SAR）研究，确定N -（3 - {1 - [4 -（3,4 - 二氟苯氧基）苄基] - 4 - 哌啶基} - 4 - 甲基苯基）- 2 - 甲基丙酰胺（16g，SNAP 94847）是MCH1受体的高亲和力和选择性配体。化合物16g在大鼠中还显示出良好的口服生物利用度（59%），并且脑/血浆比为2.3。化合物16g在体内抑制了中枢诱导的MCH诱导的饮水效应，并在大鼠社交互动模型中表现出剂量依赖性的抗焦虑作用。
