Discovery of novel hedgehog antagonists from cell-based screening: Isosteric modification of p38 bisamides as potent inhibitors of SMO.
Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38α kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics.
AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. bin.yang@astrazeneca.com
Bin
B
Yang
Alexander W
AW
Hird
Daniel John
DJ
Russell
Benjamin P
BP
Fauber
Les A
LA
Dakin
Xiaolan
X
Zheng
Qibin
Q
Su
Robert
R
Godin
Patrick
P
Brassil
Erik
E
Devereaux
James W
JW
Janetka
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004353:Drug Evaluation, Preclinical; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000577:Amides; D053823:Hedgehog Proteins; D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D048308:Mitogen-Activated Protein Kinase 14