Discovery of Potent, Selective and Reversible Caspase-3 Inhibitors
Discovery of Potent, Selective and Reversible Caspase-3 Inhibitors作者机构：Department of Medicinal Chemistry Department of Biochemistry and Molecular Biology Merck Frosst Centre for Therapeutic Research Merck Frosst Canada & Co. P.O. Box 1005 Pointe-Claire-DorvalQuebec Canada H9R 4P8
出 版 物：《合成化学》 (Chinese Journal of Synthetic Chemistry)
年 卷 期：2004年第12卷第Z1期
页 面：13-13页
主 题：programmed cell death cytoskeletal proteins molecular mechanisms identification of animal models DNA repair in vitro
摘 要：Recent studies towards understanding the molecular mechanisms of apoptosis have revealed the importance of a group of cysteinyl aspartate specific proteases, the caspases, in the programmed cell death process (Hengartner, M.O. Nature 2000, 407, 770). Caspase-3, in particular,has been characterized as the dominant effector caspase involved in the proteolytic cleavage of a variety of protein substrates including cytoskeletal proteins, kinases and DNA repair enzymes during apoptosis (Nicholson, D. W. Cell Death Differ. 1999, 6, 1028). The development of potent and selective caspase-3 inhibitors has thus emerged as an attractive therapeutic target. In the presentation,the identification of a series of potent, selective and reversible non-peptidyl caspase-3 inhibitors containing a pyrazinone core (1) will be presented. SAR optimization at R1, R2, R3 and R4 led to the discovery of inhibitors such as 2 with excellent in vitro activities (IC50 against rh-caspase-3: 5 nM; IC50 against camptothecin induced apoptotic cell death in NT2 cells: 20 nM). Compounds such as 2 also displayed excellent in vivo activities in a number of animal models of acute injuries (see: Methot, N. et al, J. Exp. Med. 2004, 119, 199; Toulmond, S. et al, British J. Pharm. 2004, 141,689; Holtzman,D.M. et al, JBC, 2002, 277, 30128), and selected examples will be discussed during the presentation.
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