Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT-957 was very recently disclosed, and trials were terminated owing to inadequate CNS concentrations to obtain a pharmacodynamic effect. The multistep synthesis of an α-ketoamide peptidomimetic inhibitor series potentially including ABT-957 was optimized to yield diastereomerically pure compounds that are potent and selective for calpain-1 over papain and cathepsins B and K. As the final oxidation step, with its optimized synthesis protocol, does not alter the configuration of the substrate, the synthesis of the diastereomeric pair (R)-1-benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 c) and (R)-1benzyl-N-((R)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 g) was feasible. This allowed the exploration of stereoselective inhibition of calpain-1, with 1 c (IC 50 = 78 nM) being significantly more potent than 1 g. Moreover, inhibitor 1 c restored cognitive function in amnestic mice.
The calpain–cathepsin hypothesis
posits a key role for elevated
calpain-1 and cathepsin-B activity in the neurodegeneration underlying
neurotrauma and multiple disorders including Alzheimer’s disease
(AD). AD clinical trials were recently halted on alicapistat, a selective
calpain-1 inhibitor, because of insufficient exposure of neurons to
the drug. In contrast to neuroprotection, the ability of calpain-1
and cathepsin-B inhibitors to protect the blood–brain barrier
(BBB), is understudied. Since cerebrovascular dysfunction underlies
vascular dementia, is caused by ischemic stroke, and is emerging as
an early feature in the progression of AD, we studied protection of
brain endothelial cells (BECs) by selective and nonselective calpain-1
and cathepsin-B inhibitors. We show these inhibitors protect both
neurons and murine BECs from ischemia–reperfusion injury. Cultures
of primary BECs from ALDH2
–/–
mice that manifest enhanced oxidative
stress were sensitive to ischemia, leading to reduced cell viability
and loss of tight junction proteins; this damage was rescued by calpain-1
and cathepsin-B inhibitors. In ALDH2
–/–
mice 24 h after
mild traumatic brain injury (mTBI), BBB damage was reflected by significantly
increased fluorescein extravasation and perturbation of tight junction
proteins, eNOS, MMP-9, and GFAP. Both calpain and cathepsin-B inhibitors
alleviated BBB dysfunction caused by mTBI. No clear advantage was
shown by selective versus nonselective calpain inhibitors in these
studies. The lack of recognition of the ability of calpain inhibitors
to protect the BBB may have led to the premature abandonment of this
therapeutic approach in AD clinical trials and requires further mechanistic
studies of cerebrovascular protection by calpain-1 inhibitors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.