Potent agonists of the Hedgehog signaling pathway.
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.
Brunton
Shirley A
SA
Evotec, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, UK. shirley.brunton@evotec.com
Stibbard
John H A
JH
Rubin
Lee L
LL
Guicherit
Oivin M
OM
Kruse
Lawrence I
LI
Price
Stephen
S
di Lucrezia
Raffaella
R
MacKinnon
Colin H
CH
Avery
Alaric
A
Park
Yvonne
Y
Buxton
Danielle
D
Boyd
Edward A
EA
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
D002264:Carboxylic Acids; D053823:Hedgehog Proteins; D013876:Thiophenes; C088015:benzothiophene