title: Discovery of orally bioavailable 1,3,4-trisubstituted 2-oxopiperazine-based melanocortin-4 receptor agonists as potential antiobesity agents.
abstract: A study that was designed to identify plausible replacements for highly basic guanidine moiety contained in potent MC4R agonists, as exemplified by 1, led to the discovery of initial nonguanidine lead 5. Propyl analog 23 was subsequently found to be equipotent to 5, whereas analogs bearing smaller and branched alkyl groups at the 3 position of the oxopiperazine template demonstrated reduced binding affinity and agonist potency for MC4R. Acylation of the NH2 group of the 4F-D-Phe residue of 3-propyl analog 23 significantly increased the binding affinity and the functional activity for MC4R. Analogs with neutral and weakly basic capping groups of the D-Phe residue exhibited excellent MC4R selectivity against MC1R whereas those with an amino acid had moderate MC4R/MC1R selectivity. We have also demonstrated that compound 35 showed promising oral bioavailability and a moderate oral half life and induced significant weight loss in a 28-day rat obesity model.
authors.affiliation: Procter & Gamble Pharmaceuticals, Global Business & New Technology Development, Mason, Ohio 45040, USA. xinrong.2.tian@gsk.com
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tian
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Switzer
authors.forename: Steve A
authors.initials: SA
authors.lastname: Derose
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Mishra
authors.forename: Mark G
authors.initials: MG
authors.lastname: Solinsky
authors.forename: Rashid N
authors.initials: RN
authors.lastname: Mumin
authors.forename: Frank H
authors.initials: FH
authors.lastname: Ebetino
authors.forename: Lalith R
authors.initials: LR
authors.lastname: Jayasinghe
authors.forename: Mark E
authors.initials: ME
authors.lastname: Webster
authors.forename: Anny-Odile
authors.initials: AO
authors.lastname: Colson
authors.forename: Doreen
authors.initials: D
authors.lastname: Crossdoersen
authors.forename: Beth B
authors.initials: BB
authors.lastname: Pinney
authors.forename: Julie A
authors.initials: JA
authors.lastname: Farmer
authors.forename: Martin E
authors.initials: ME
authors.lastname: Dowty
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Obringer
authors.forename: Charles A
authors.initials: CA
authors.lastname: Cruze
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Burklow
authors.forename: Paula M
authors.initials: PM
authors.lastname: Suchanek
authors.forename: Lily
authors.initials: L
authors.lastname: Dong
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Dirr
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Sheldon
authors.forename: John A
authors.initials: JA
authors.lastname: Wos
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001682:Biological Availability; D004032:Diet; D004195:Disease Models, Animal; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004435:Eating / Q000187:drug effects; D008297:Male; D008968:Molecular Conformation; D009765:Obesity / Q000188:drug therapy*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D013237:Stereoisomerism
chemical_list: D019440:Anti-Obesity Agents; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4