title: Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1-R) antagonists.
abstract: 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 MCH1R 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 MCH1R antagonist which led to a reduction of food intake in an acute feeding assay paradigm.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, RY121E-22, Rahway, NJ 07065-0900, USA. robert_devita@merck.com
authors: Robert J
authors: RJ
authors: DeVita
mesh_terms: D000586:Amination; D000634:Aminoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D006801:Humans; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor