title: Synthesis and biological evaluation of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R).
abstract: A novel series of imidazole-based small molecule antagonists of the melanocortin 4 receptor (MC4-R) is reported. Members of this series have been identified, which exhibit sub-micromolar binding affinity for the MC4-R, functional potency <100nM, and good oral exposure in rat. Antagonists of the MC4-R are potentially useful in the therapeutic treatment of involuntary weight loss due to advanced age or disease (e.g. cancer or AIDS), an area of large, unmet medical need.
authors.affiliation: Department of Medicinal Chemistry, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA. tmarsiljie@gnf.org
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Marsilje
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Roses
authors.forename: Emily F
authors.initials: EF
authors.lastname: Calderwood
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Stroud
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Forsyth
authors.forename: Christopher
authors.initials: C
authors.lastname: Blackburn
authors.forename: David L
authors.initials: DL
authors.lastname: Yowe
authors.forename: Wenyan
authors.initials: W
authors.lastname: Miao
authors.forename: Stacey V
authors.initials: SV
authors.lastname: Drabic
authors.forename: Marie D
authors.initials: MD
authors.lastname: Bohane
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patane
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Claiborne
mesh_terms: D000818:Animals; D001665:Binding Sites; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D044105:Receptor, Melanocortin, Type 4; C029899:imidazole