Novel 2-phenylquinolin-7-yl-derived imidazo[1,5-a]pyrazines as potent insulin-like growth factor-I receptor (IGF-IR) inhibitors.
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.
Mulvihill
Mark J
MJ
(OSI) Oncology, OSI Pharmaceuticals, Inc., 41 Pinelawn Road, Melville, NY 11747, USA. mmulvihill@osip.com
Ji
Qun-Sheng
QS
Coate
Heather R
HR
Cooke
Andrew
A
Dong
Hanqing
H
Feng
Lixin
L
Foreman
Kenneth
K
Rosenfeld-Franklin
Maryland
M
Honda
Ayako
A
Mak
Gilda
G
Mulvihill
Kristen M
KM
Nigro
Anthony I
AI
O'Connor
Matthew
M
Pirrit
Caroline
C
Steinig
Arno G
AG
Siu
Kam
K
Stolz
Kathryn M
KM
Sun
Yingchuan
Y
Tavares
Paula A R
PA
Yao
Yan
Y
Gibson
Neil W
NW
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
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