title: Spiroindane based amides as potent and selective MC4R agonists for the treatment of obesity.
abstract: We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. shuwen_he@merck.com
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Ye
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dobbelaar
authors.forename: Iyassu K
authors.initials: IK
authors.lastname: Sebhat
authors.forename: Liangqin
authors.initials: L
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Tianying
authors.initials: T
authors.lastname: Jian
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Lai
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Franklin
authors.forename: Raman K
authors.initials: RK
authors.lastname: Bakshi
authors.forename: James P
authors.initials: JP
authors.lastname: Dellureficio
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Hong
authors.forename: David H
authors.initials: DH
authors.lastname: Weinberg
authors.forename: Tanya
authors.initials: T
authors.lastname: Macneil
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
authors.forename: Qianping
authors.initials: Q
authors.lastname: Peng
authors.forename: Randy R
authors.initials: RR
authors.lastname: Miller
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Stearns
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chen
authors.forename: Airu S
authors.initials: AS
authors.lastname: Chen
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy*; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D019440:Anti-Obesity Agents; C470072:MC4R protein, human; C553253:MK-0489; D011759:Pyrrolidines; D044105:Receptor, Melanocortin, Type 4; D013141:Spiro Compounds