title: Potent agonists of the Hedgehog signaling pathway.
abstract: A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane group is shown to be exquisitely sensitive to substitution on the 4-amino group, and SAR for the 3-chlorobenzothiophene group is highly specific. Preliminary SAR studies of the biaryl substituent led to a picomolar compound with in vivo activity.
authors.affiliation: Evotec, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, UK. shirley.brunton@evotec.com
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Brunton
authors.forename: John H A
authors.initials: JH
authors.lastname: Stibbard
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: Oivin M
authors.initials: OM
authors.lastname: Guicherit
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Kruse
authors.forename: Stephen
authors.initials: S
authors.lastname: Price
authors.forename: Raffaella
authors.initials: R
authors.lastname: di Lucrezia
authors.forename: Colin H
authors.initials: CH
authors.lastname: MacKinnon
authors.forename: Alaric
authors.initials: A
authors.lastname: Avery
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Park
authors.forename: Danielle
authors.initials: D
authors.lastname: Buxton
authors.forename: Edward A
authors.initials: EA
authors.lastname: Boyd
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D053823:Hedgehog Proteins / Q000819:agonists* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D020521:Stroke / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D053823:Hedgehog Proteins; D013876:Thiophenes; C088015:benzothiophene