Design and synthesis of 4-quinolinone 2-carboxamides as calpain inhibitors.

Dong Hyuk Nam, Kwang Seob Lee, Sang Hoon Kim, Sung Min Kim, Seo Yun Jung, Sung Hyun Chung, Hyoung Ja Kim, Nam Doo Kim, Changbae Jin, Yong Sup Lee

Index: Bioorg. Med. Chem. Lett. 18 , 205-209, (2008)

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Abstract

Calpains are involved in a variety of calcium-regulated cellular processes, such as signal transduction, cell proliferation, differentiation, and apoptosis. Excessive calpain activation contributes to serious cellular damage and has been reported in many pathological conditions. 4-Quinolinone 2-carboxamide derivatives were prepared and evaluated for mu-calpain inhibitory activities. Of the compounds synthesized, 3a and 3k, which possess a primary amide and 4-methoxyphenethyl amide at P1' region, were found to most potently inhibit mu-calpain with IC50 values of 0.71+/-0.07 and 0.73+/-0.23 microM, respectively. On the other hand, the incorporation of pyridine-containing amides decreased inhibitory activity.