title: Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor.
abstract: Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, MSD Ltd, Newhouse, Lanarkshire ML1 5SH, UK. angus.morrison@merck.com
authors.forename: Angus J
authors.initials: AJ
authors.lastname: Morrison
authors.forename: Julia M
authors.initials: JM
authors.lastname: Adam
authors.forename: James A
authors.initials: JA
authors.lastname: Baker
authors.forename: Robert A
authors.initials: RA
authors.lastname: Campbell
authors.forename: John K
authors.initials: JK
authors.lastname: Clark
authors.forename: Jean E
authors.initials: JE
authors.lastname: Cottney
authors.forename: Maureen
authors.initials: M
authors.lastname: Deehan
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Easson
authors.forename: Ruth
authors.initials: R
authors.lastname: Fields
authors.forename: Stuart
authors.initials: S
authors.lastname: Francis
authors.forename: Fiona
authors.initials: F
authors.lastname: Jeremiah
authors.forename: Neil
authors.initials: N
authors.lastname: Keddie
authors.forename: Takao
authors.initials: T
authors.lastname: Kiyoi
authors.forename: Duncan R
authors.initials: DR
authors.lastname: McArthur
authors.forename: Karsten
authors.initials: K
authors.lastname: Meyer
authors.forename: Paul D
authors.initials: PD
authors.lastname: Ratcliffe
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schulz
authors.forename: Grant
authors.initials: G
authors.lastname: Wishart
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yoshiizumi
mesh_terms: D000818:Animals; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D006571:Heterocyclic Compounds; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; D013830:Thiadiazoles