2. Academic Validation
  3. Melanin-concentrating hormone receptor 1 antagonists: synthesis, structure-activity relationship, docking studies, and biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives

Melanin-concentrating hormone receptor 1 antagonists: synthesis, structure-activity relationship, docking studies, and biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives

  • Bioorg Med Chem. 2011 Nov 1;19(21):6261-73. doi: 10.1016/j.bmc.2011.09.007.
Shizuo Kasai 1,  Masahiro Kamaura,  Makoto Kamata,  Kazuyoshi Aso,  Hitomi Ogino,  Yoshihide Nakano,  Kaoru Watanabe,  Tomoko Kaisho,  Michiko Tawada,  Yasutaka Nagisa,  Shiro Takekawa,  Koki Kato,  Nobuhiro Suzuki,  Yuji Ishihara
Affiliations

Affiliation

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1 Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. [email protected]
PMID: 21975069 DOI: 10.1016/j.bmc.2011.09.007
Abstract

Melanin-concentrating hormone receptor 1 (MCHR1) antagonists have been studied as potential agents for the treatment of obesity. Initial structure-activity relationship studies of in-house hit compound 1a and subsequent optimization studies resulted in the identification of tetrahydroisoquinoline derivative 23, 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-[4-(4-chlorophenyl)piperidin-1-yl]butan-1-one, as a potent hMCHR1 antagonist. A homology model of hMCHR1 suggests that these compounds interact with Asn 294 and Asp 123 in the binding site of hMCHR1 to enhance binding affinity. Oral administration of compound 23 dose-dependently reduced food intake in diet-induced obesity (DIO)-F344 rats.

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