1. Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury
- Author
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Elise Sudbeck, Jason Katz, Adam Kois, Brydon L. Bennett, Steven S. Clareen, Michael A. Shirley, Rachel Fan, Shripad S. Bhagwat, Jonathan Wright, Ronald Albers, Brian E. Cathers, Maria Celeridad, Lisa Nadolny, Yang Tang, Sogole Bahmanyar, Heather Raymon, Sutapa Ghosh, David Giegel, Henderson Ian, Philip P Chamberlain, Mehran F. Moghaddam, Kevin S. Hughes, Brent Benish, Kate Blease, Sema Pai, Veronique Plantevin Krenitsky, Jacek Nowakowski, Robert Hilgraf, Mercedes Delgado, Paul Omholt, Yoshitaka Satoh, Jeff Muir, Kiran Sahasrabudhe, Leticia Ayala, Andrew G. Cole, Oleg Khatsenko, and Li Xu
- Subjects
Models, Molecular ,Clinical Biochemistry ,Ischemia ,Pharmaceutical Science ,2-Aminopurine ,Pharmacology ,Biochemistry ,Enzyme activator ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Dogs ,Catalytic Domain ,Drug Discovery ,medicine ,Potency ,Structure–activity relationship ,Animals ,Enzyme Inhibitors ,Molecular Biology ,Molecular Structure ,Chemistry ,Kinase ,Organic Chemistry ,JNK Mitogen-Activated Protein Kinases ,Haplorhini ,medicine.disease ,Rats ,Enzyme Activation ,Purines ,Reperfusion Injury ,Molecular Medicine ,Reperfusion injury ,Aminopurine - Abstract
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
- Published
- 2011