Synthesis and c-Src inhibitory activity of imidazo[1,5- a]pyrazine derivatives as an agent for treatment of acute ischemic stroke

• Published in: Bioorganic & medicinal chemistry 2007-01, Vol.15 (2), p.868-885
• Main Authors: Mukaiyama, Harunobu, Nishimura, Toshihiro, Kobayashi, Satoko, Ozawa, Tomonaga, Kamada, Noboru, Komatsu, Yoshimitsu, Kikuchi, Shinji, Oonota, Hideki, Kusama, Hiroshi
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Brain ischemia; Brain Ischemia - complications; c-Src; Central nervous system (CNS) penetration; CH–π interaction; Crystallography, X-Ray; Enzyme Inhibitors - blood; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Humans; Imidazo[1,5- a]pyrazine; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Indicators and Reagents; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Molecular Conformation; Neuroprotective Agents - blood; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - pharmacology; Pyrazines - chemical synthesis; Pyrazines - pharmacology; Rats; Spectrophotometry, Infrared; src-Family Kinases - antagonists & inhibitors; Stroke - drug therapy; Stroke - etiology; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.10.041

We studied novel c-Src inhibitors as potential therapeutic agents for acute ischemic stroke. Compound 14c· HCl demonstrated potent c-Src inhibitory activity, remarkable central nervous system (CNS) penetration, and significant neuroprotective efficacy in vivo in rat models. We synthesized and evaluated a series of C-5 substituted imidazo[1,5- a]pyrazine derivatives to identify potent c-Src inhibitors as potential therapeutic agents for acute ischemic stroke. Among these compounds, compound 14c· HCl demonstrated remarkable central nervous system (CNS) penetration and significant neuroprotective efficacy in vivo in rat models.