title: Synthesis and SAR of derivatives based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity.
abstract: This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. jian_liu@merck.com
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.forename: Tianying
authors.initials: T
authors.lastname: Jian
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dobbelaar
authors.forename: Iyassu K
authors.initials: IK
authors.lastname: Sebhat
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: Allan
authors.initials: A
authors.lastname: Goodman
authors.forename: Cheng
authors.initials: C
authors.lastname: Guo
authors.forename: Peter R
authors.initials: PR
authors.lastname: Guzzo
authors.forename: Mark
authors.initials: M
authors.lastname: Hadden
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Henderson
authors.forename: Kevin
authors.initials: K
authors.lastname: Pattamana
authors.forename: Megan
authors.initials: M
authors.lastname: Ruenz
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Sargent
authors.forename: Brian
authors.initials: B
authors.lastname: Swenson
authors.forename: Larry
authors.initials: L
authors.lastname: Yet
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
authors.forename: Qianping
authors.initials: Q
authors.lastname: Peng
authors.forename: Jie
authors.initials: J
authors.lastname: Pan
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Kan
authors.forename: Oksana
authors.initials: O
authors.lastname: Palyha
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Kelly
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Guan
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: Marc L
authors.initials: ML
authors.lastname: Reitman
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D018004:Receptors, Bombesin / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C550526:2-(2-(4-(pyridin-2-yl)phenyl)ethyl)-5-(2,2-dimethylbutyl)-1H-imidazole; D007093:Imidazoles; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3