Potent inhibition of Ca2+-dependent activation of calpain-1 by novel mercaptoacrylates

Calpain-1 is a Ca2+-activated cytosolic cysteine protease. Its activation has been linked to extravasation into inflamed tissue of white blood cells, especially neutrophils. Calpain-1 may therefore be an anti-inflammatory target for therapeutic intervention. 24 novel monohalogenated phenyl and indole mercaptoacrylic acid derivatives were synthesised. The location and nature of the ring-coupled halides strongly influenced the potency of these compounds to inhibit calpain activation. Several of the calpain-1 inhibitors showed IC50 values in the low nanomolar range and prevented cell shape change of neutrophils, a necessary prelude to their migration from the blood in the body.