title: Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA. stefan.peukert@novartis.com
authors.forename: Stefan
authors.initials: S
authors.lastname: Peukert
authors.forename: Rishi K
authors.initials: RK
authors.lastname: Jain
authors.forename: Adrian
authors.initials: A
authors.lastname: Geisser
authors.forename: Yingchuan
authors.initials: Y
authors.lastname: Sun
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Aaron
authors.initials: A
authors.lastname: Bourret
authors.forename: Adam
authors.initials: A
authors.lastname: Carlson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dasilva
authors.forename: Arun
authors.initials: A
authors.lastname: Ramamurthy
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Kelleher
mesh_terms: 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
chemical_list: 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