14714-31-9Relevant articles and documents
Discovery, synthesis, and structure-activity relationship of 6-aminomethyl-7,8-dihydronaphthalenes as human melanin-concentrating hormone receptor 1 antagonists
Kamata, Makoto,Yamashita, Toshiro,Imaeda, Toshihiro,Tanaka, Toshio,Terauchi, Jun,Miyamoto, Maki,Ora, Taiichi,Tawada, Michiko,Endo, Satoshi,Takekawa, Shiro,Asami, Asano,Suzuki, Nobuhiro,Nagisa, Yasutaka,Nakano, Yoshihide,Watanabe, Kaoru,Ogino, Hitomi,Kato, Koki,Kato, Kaneyoshi,Ishihara, Yuji
, p. 5539 - 5552 (2011/10/17)
Human melanin-concentrating hormone receptor 1 (hMCHR1) antagonists are promising targets for obesity treatment. We identified the tetrahydronaphthalene derivative 1a with modest binding affinity for hMCHR1 by screening an in-house G protein-coupled receptor (GPCR) ligand library. We synthesized a series of 6-aminomethyl-5,6,7,8-tetrahydronaphthalenes and evaluated their activity as hMCHR1 antagonists. Modification of the biphenylcarbonylamino group revealed that the biphenyl moiety played a crucial role in the interaction of the antagonist with the receptor. The stereoselective effect of the chiral center on binding affinity generated the novel 6-aminomethyl-7,8-dihydronaphthalene scaffold without a chiral center. Optimization of the amino group led to the identification of a potent antagonist 2s (4′-fluoro-N-[6-(1- pyrrolidinylmethyl)-7,8-dihydro-2-naphthalenyl][1,1′-biphenyl] -4-carboxamide), which significantly inhibited the nocturnal food intake in rats after oral administration. Pharmacokinetic analysis confirmed that 2s had good oral bioavailability and brain penetrance. This antagonist appears to be a viable lead compound that can be used to develop a promising therapy for obesity.
