Author/Authors :
Mark J. Mulvihill، نويسنده , , Qun-Sheng Ji، نويسنده , , Heather R. Coate، نويسنده , , Andrew Cooke، نويسنده , , Hanqing Dong، نويسنده , , Lixin Feng، نويسنده , , Kenneth Foreman، نويسنده , , Maryland Rosenfeld-Franklin، نويسنده , , Ayako Honda، نويسنده , , Gilda Mak، نويسنده , , Kristen M. Mulvihill، نويسنده , , Anthony I. Nigro، نويسنده , , Matthew O’Connor، نويسنده , , Caroline Pirrit، نويسنده , , Arno G. Steinig، نويسنده , , Kam Siu، نويسنده , , Kathryn M. Stolz، نويسنده , , Yingchuan Sun، نويسنده , , Paula A.R. Tavares، نويسنده , , Jia-Yan Yao ، نويسنده , , et al.، نويسنده ,
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.
Keywords :
Imidazopyrazines , IGF-IR , IGF-1R , Tyrosine kinase inhibitor , Tumor growth inhibition , Cancer , Insulin-like growth factor-I receptor
