title: Novel 2-phenylquinolin-7-yl-derived imidazo[1,5-a]pyrazines as potent insulin-like growth factor-I receptor (IGF-IR) inhibitors.
abstract: A series of novel, potent quinolinyl-derived imidazo[1,5-a]pyrazine IGF-IR (IGF-1R) inhibitors--most notably, cis-3-(3-azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine (AQIP)--is described. Synthetic details, structure-activity relationships, and in vitro biological activity are reported for the series. Key in vitro and in vivo biological results for AQIP are reported, including: inhibition of ligand-stimulated autophosphorylation of IGF-IR and downstream pathways in 3T3/huIGFIR cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; a pharmacokinetic profile suitable for once-per-day oral dosing; antitumor activity in a 3T3/huIGFIR xenograft model; and effects on insulin and glucose levels.
authors.affiliation: (OSI) Oncology, OSI Pharmaceuticals, Inc., 41 Pinelawn Road, Melville, NY 11747, USA. mmulvihill@osip.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulvihill
authors.forename: Qun-Sheng
authors.initials: QS
authors.lastname: Ji
authors.forename: Heather R
authors.initials: HR
authors.lastname: Coate
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.forename: Hanqing
authors.initials: H
authors.lastname: Dong
authors.forename: Lixin
authors.initials: L
authors.lastname: Feng
authors.forename: Kenneth
authors.initials: K
authors.lastname: Foreman
authors.forename: Maryland
authors.initials: M
authors.lastname: Rosenfeld-Franklin
authors.forename: Ayako
authors.initials: A
authors.lastname: Honda
authors.forename: Gilda
authors.initials: G
authors.lastname: Mak
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Mulvihill
authors.forename: Anthony I
authors.initials: AI
authors.lastname: Nigro
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Connor
authors.forename: Caroline
authors.initials: C
authors.lastname: Pirrit
authors.forename: Arno G
authors.initials: AG
authors.lastname: Steinig
authors.forename: Kam
authors.initials: K
authors.lastname: Siu
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Stolz
authors.forename: Yingchuan
authors.initials: Y
authors.lastname: Sun
authors.forename: Paula A R
authors.initials: PA
authors.lastname: Tavares
authors.forename: Yan
authors.initials: Y
authors.lastname: Yao
authors.forename: Neil W
authors.initials: NW
authors.lastname: Gibson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry*; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001786:Blood Glucose; D007093:Imidazoles; D007328:Insulin; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011804:Quinolines; C517813:imidazo(1,5-a)pyrazine; D017526:Receptor, IGF Type 1