Identification of 4-amino-2-cyclohexylaminoquinazolines as metabolically stable melanin-concentrating hormone receptor 1 antagonists

Through an optimization of the distance between two key pharmacophore features, 4-amino-2-cyclohexylaminoquinazolines were identified as potent melanin-concentrating hormone receptor 1 (MCH-R1) antagonists, leading to the discovery of ATC0065. The optimization of the distance between two key pharmacophore features within our first hit compounds 1a and 2a led to the identification of a new class of potent non-peptidic antagonists for the MCH-R1, based around 4-amino-2-cyclohexylaminoquinazolines. In particular, ATC0065 ( 2c), N 2-[ cis-4-({2-[4-Bromo-2-(trifluoromethoxy)phenyl]ethyl}amino)cyclohexyl]- N 4, N 4-dimethylquinazoline-2,4-diamine dihydrochloride, bound with high affinity to the MCH-R1 (IC 50 value of 16 nM) and showed good metabolic stability in liver microsomes from human and rat.