title: Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.
abstract: We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, MSD Ltd, Newhouse, Lanarkshire, ML1 5SH, UK. Paul.Ratcliffe@grunenthal.com
authors.forename: Paul
authors.initials: P
authors.lastname: Ratcliffe
authors.forename: Julia M
authors.initials: JM
authors.lastname: Adam
authors.forename: James
authors.initials: J
authors.lastname: Baker
authors.forename: Roberta
authors.initials: R
authors.lastname: Bursi
authors.forename: Robert
authors.initials: R
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: Daniel
authors.initials: D
authors.lastname: Ecker
authors.forename: Darren
authors.initials: D
authors.lastname: Edwards
authors.forename: Ola
authors.initials: O
authors.lastname: Epemolu
authors.forename: Louise
authors.initials: L
authors.lastname: Evans
authors.forename: Ruth
authors.initials: R
authors.lastname: Fields
authors.forename: Stuart
authors.initials: S
authors.lastname: Francis
authors.forename: Paul
authors.initials: P
authors.lastname: Harradine
authors.forename: Fiona
authors.initials: F
authors.lastname: Jeremiah
authors.forename: Takao
authors.initials: T
authors.lastname: Kiyoi
authors.forename: Duncan
authors.initials: D
authors.lastname: McArthur
authors.forename: Angus
authors.initials: A
authors.lastname: Morrison
authors.forename: Paul
authors.initials: P
authors.lastname: Passier
authors.forename: Jack
authors.initials: J
authors.lastname: Pick
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schnabel
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schulz
authors.forename: Heinz
authors.initials: H
authors.lastname: Steinbrede
authors.forename: Glenn
authors.initials: G
authors.lastname: Walker
authors.forename: Paul
authors.initials: P
authors.lastname: Westwood
authors.forename: Grant
authors.initials: G
authors.lastname: Wishart
authors.forename: Joanna
authors.initials: J
authors.lastname: Udo de Haes
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007211:Indoles / Q000737:chemistry*; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D006571:Heterocyclic Compounds; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; D013844:Thiazoles; C030374:indole; D003577:Cytochrome P-450 Enzyme System