title: Design of 1-piperazinyl-4-arylphthalazines as potent Smoothened antagonists.
abstract: The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.
authors.affiliation: Department of Medicinal Chemistry, AMGEN, S. San Francisco, CA 94080, USA. blucas@amgen.com
authors.forename: Brian S
authors.initials: BS
authors.lastname: Lucas
authors.forename: Wade
authors.initials: W
authors.lastname: Aaron
authors.forename: Songzhu
authors.initials: S
authors.lastname: An
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Austin
authors.forename: Matthew
authors.initials: M
authors.lastname: Brown
authors.forename: Hon
authors.initials: H
authors.lastname: Chan
authors.forename: Angela
authors.initials: A
authors.lastname: Chong
authors.forename: Randall
authors.initials: R
authors.lastname: Hungate
authors.forename: Tom
authors.initials: T
authors.lastname: Huang
authors.forename: Ben
authors.initials: B
authors.lastname: Jiang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Kaizerman
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Dustin L
authors.initials: DL
authors.lastname: McMinn
authors.forename: Jessica
authors.initials: J
authors.lastname: Orf
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
authors.forename: Minqing
authors.initials: M
authors.lastname: Rong
authors.forename: Maria M
authors.initials: MM
authors.lastname: Toteva
authors.forename: Craig
authors.initials: C
authors.lastname: Uyeda
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
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D015195:Drug Design; D053823:Hedgehog Proteins; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D000072086:Smoothened Receptor
chemical_list: D053823:Hedgehog Proteins; D010793:Phthalazines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D003577:Cytochrome P-450 Enzyme System