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.
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Blood Glucose / metabolism
-
Cell Line
-
Dogs
-
Female
-
Humans
-
Imidazoles / chemical synthesis*
-
Imidazoles / chemistry
-
Imidazoles / pharmacology*
-
Insulin / blood
-
Ligands
-
Mice
-
Molecular Structure
-
Protein Kinase Inhibitors / chemical synthesis*
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology*
-
Pyrazines / chemical synthesis*
-
Pyrazines / chemistry
-
Pyrazines / pharmacology*
-
Quinolines / chemistry*
-
Rats
-
Receptor, IGF Type 1 / antagonists & inhibitors*
-
Receptor, IGF Type 1 / genetics
-
Receptor, IGF Type 1 / metabolism
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
Blood Glucose
-
Imidazoles
-
Insulin
-
Ligands
-
Protein Kinase Inhibitors
-
Pyrazines
-
Quinolines
-
imidazo(1,5-a)pyrazine
-
Receptor, IGF Type 1