Graczyk Piotr P
Department of Medicinal Chemistry, EISAI London Research Laboratories, University College London, Bernard Katz Building, London WC1E 6BT, UK.
Prog Med Chem. 2002;39:1-72. doi: 10.1016/s0079-6468(08)70068-7.
The striking efficacy of Z-VAD-fmk in the various animal models presented above may reflect its ability to inhibit multiple enzymes including caspases. In accord with this, more selective, reversible inhibitors usually show low efficacy in multifactorial models such as ischaemia, but may offer some protection against NMDA-induced excitotoxicity and hepatitis. Importantly, caspase inhibitors may exhibit significant activity in vivo even when they are applied post insult. As far as the CNS is concerned, the first systemically active inhibitors have emerged. Functional recovery could be achieved in some ischaemia models, but long-term protection by caspase inhibitors is still being questioned. Recent developments in drug design enabled the first caspase inhibitors to enter the clinic. Although initially directed towards peripheral indications such as rheumatoid arthritis, caspase inhibitors will no doubt eventually be used to target CNS disorders. For this purpose the peptidic character of current inhibitors will have to be further reduced. Small molecule, nonpeptidic caspase inhibitors, which have appeared recently, indicate that this goal can be accomplished. Unfortunately, many fundamental questions still remain to be addressed. In particular, the necessary spectrum of inhibitory activity required to achieve the desired effect needs to be determined. There is also a safety aspect associated with prolonged administration. Therefore, the next therapeutic areas for broader-range caspase inhibitors are likely to involve acute treatment. Recent results with synergistic effects between MK-801 and caspase inhibitors in ischaemia suggest that caspase inhibitors may need to be used in conjunction with other drugs. It can be expected that, in the near future, research on caspases and their inhibitors will remain a rapidly developing area of biology and medicinal chemistry. More time, however, may be needed for the first caspase inhibitors to appear on the market.
