title: Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.
abstract: An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.
authors.affiliation: Department of Chemistry, Amgen San Francisco, South San Francisco, CA 94080, USA. jmihalic@amgen.com
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Mihalic
authors.forename: Pingchen
authors.initials: P
authors.lastname: Fan
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Chen
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.forename: Alykhan
authors.initials: A
authors.lastname: Motani
authors.forename: Lingming
authors.initials: L
authors.lastname: Liang
authors.forename: Michelle
authors.initials: M
authors.lastname: Lindstrom
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Chen
authors.forename: Juan
authors.initials: J
authors.lastname: Jaen
authors.forename: Kang
authors.initials: K
authors.lastname: Dai
authors.forename: Leping
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D059305:Diet, High-Fat; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002227:Carbazoles; D003509:Cyclohexanecarboxylic Acids; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor