title: Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines.
abstract: Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.
authors.affiliation: Amgen, Inc., South San Francisco, CA 94080, USA.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Kaizerman
authors.forename: Wade
authors.initials: W
authors.lastname: Aaron
authors.forename: Songzhu
authors.initials: S
authors.lastname: An
authors.forename: Richard
authors.initials: R
authors.lastname: Austin
authors.forename: Matt
authors.initials: M
authors.lastname: Brown
authors.forename: Angela
authors.initials: A
authors.lastname: Chong
authors.forename: Tom
authors.initials: T
authors.lastname: Huang
authors.forename: Randall
authors.initials: R
authors.lastname: Hungate
authors.forename: Ben
authors.initials: B
authors.lastname: Jiang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Brian S
authors.initials: BS
authors.lastname: Lucas
authors.forename: Jessica
authors.initials: J
authors.lastname: Orf
authors.forename: Minqing
authors.initials: M
authors.lastname: Rong
authors.forename: Maria M
authors.initials: MM
authors.lastname: Toteva
authors.forename: Dineli
authors.initials: D
authors.lastname: Wickramasinghe
authors.forename: Guifen
authors.initials: G
authors.lastname: Xu
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.forename: Wendy
authors.initials: W
authors.lastname: Zhong
authors.forename: Dustin L
authors.initials: DL
authors.lastname: McMinn
mesh_terms: D000818:Animals; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000077297:Pregnane X Receptor; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D011987:Receptors, Steroid / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship; D015645:Tylosin / Q000031:analogs & derivatives
chemical_list: C114856:4-'demycarosyl-20-deoxo-20-(di-N-benzylamino)-8a-aza-8a-homotylosin; C553441:4-(4-phenylphthalazine-1-yl)piperazine amide; D053823:Hedgehog Proteins; D010793:Phthalazines; D010879:Piperazines; D000077297:Pregnane X Receptor; D011724:Pyridazines; D043562:Receptors, G-Protein-Coupled; D011987:Receptors, Steroid; C491023:SMO protein, human; D000072086:Smoothened Receptor; C062482:pyridazine; C043388:phthalazine; D015645:Tylosin