Identification and neuroprotective properties of NA-184, a selective calpain-2 inhibitor

Our laboratory has shown that calpain-2 activation in the brain following acute injury is directly related to neuronal damage and the long-term functional consequences of the injury, while calpain-1 activation is generally neuroprotective and calpain-1 deletion exacerbates neuronal injury. We have also shown that a relatively selective calpain-2 inhibitor, referred to as C2I, enhanced long-term potentiation and learning and memory, and provided neuroprotection in the controlled cortical impact (CCI) model of traumatic brain injury (TBI) in mice. Similar results were also obtained in conditional calpain-2 knock-out mice. Using molecular dynamic simulation and Site Identification by Ligand Competitive Saturation (SILCS) software, we report here the discovery of a selective calpain-2 inhibitor NA-184, (S)-2-(3-benzylureido)-N-((R,S)-1-((3-chloro-2-methoxybenzyl)amino)-1,2-dioxopentan-3-yl)-4-methylpentanamide whose properties make it a good clinical candidate for the treatment of TBI.