Exploration of orally available calpain inhibitors 2: Peptidyl hemiacetal derivatives

We previously reported a potent calpain inhibitor 1 ( SJA6017, N-( 4-fluorophenyl)-L-valyl-L-leucinal), which displayed relatively low oral bioavailability ( BA). Replacing the metabolically labile aldehyde moiety of 1 with more chemically stable warheads, such as a cyclic hemiacetal, hydrazone, and alpha-ketoamide, provided the inhibitors with improved in vitro metabolic stability. Cyclic hemiacetal 2 was the most stable of these compounds. The optimization of 2 led to hemiacetal 8 ( SNJ-1715) which exhibited high potency, good aqueous solubility, excellent oral BA, and prolonged plasma half-life in rats. Furthermore, 8 showed neuroprotective efficacy via oral administration in a rat retinal ischemia model.