Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1-R) antagonists

Structure-activity relationships of a 4-aminoquinoline MCH-1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4- and 6-positions of the original HTS hit, Improvements to the original screening lead were made by addition of lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl and hydrocinnamyl carboxamides at the 6-position. Viable modifications of the 4-amino group were limited and did not allow further optimization of the physical-chemical properties of this class of compounds. Transposition of the 4-amino group to the 2-position of the quinoline core structure provided the 2-aminoquinoline lead class with similar MCH-1R binding affinity. A series of 2-aminoquinoline compounds was prepared and evaluated in MCH-1R binding and functional antagonist assays, Small dialkyl, methylalkyl, methylcycloalkyl and cyclic amines along with 3-substituted pyrrolidines were tolerated at the quinoline 2-position. The in vivo efficacy of compound A was explored and compared to that of a related inactive compound B to determine their effects on food intake and body weight in rodents. The biological activities of this matched active inactive pair provide in vivo proof of concept in rodents that antagonism of MCH1R by a 2-aminoquinoline MCF1R antagonist which led to a reduction of food intake in an acute feeding assay paradigm.