Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway.
Ortho-biphenyl carboxamides, originally prepared as inhibitors of microsomal triglyceride transfer protein (MTP) have been identified as novel inhibitors of the Hedgehog signaling pathway. Structure-activity relationship studies for this class of compounds reduced MTP inhibitory activity and led to low nanomolar Hedgehog inhibitors. Binding assays revealed that the compounds act as antagonists of Smoothened and show cross-reactivity for both the human and mouse receptor.
Peukert
Stefan
S
Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA. stefan.peukert@novartis.com
Jain
Rishi K
RK
Geisser
Adrian
A
Sun
Yingchuan
Y
Zhang
Rui
R
Bourret
Aaron
A
Carlson
Adam
A
Dasilva
Jennifer
J
Ramamurthy
Arun
A
Kelleher
Joseph F
JF
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship
D000577:Amides; D002352:Carrier Proteins; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C106092:microsomal triglyceride transfer protein