(1S,2R)-Alicapistat ((1S,2R)-ABT-957) is a highly efficient, orally active compound that selectively inhibits human calpains 1 and 2, showing promise for Alzheimer's disease (AD) therapy [1]. It effectively addresses the metabolic liability associated with carbonyl reduction and demonstrates potent inhibition of calpain 1 with an IC50 value of 395 nM [2].

(1S,2R)-Alicapistat fails to achieve sufficient concentrations in the central nervous system (CNS) for a pharmacodynamic effect [1]. It inhibits Calpain 1 (μ-calpain) and 2 (m-calpain) in a calcium-dependent manner, requiring μ-molar or m-molar calcium concentrations for activation. At 100 nM, (1S,2R)-Alicapistat (compound 22) prevents deficits in synaptic transmission caused by Aβ oligomer in rats [2]. Furthermore, at 385 nM, it effectively prevents NMDA-induced neurodegeneration and amyloid beta (Aβ)-induced synaptic dysfunction [2]. At concentrations ranging from 9-21 nM in cerebrospinal fluid (CSF), (1S,2R)-Alicapistat does not reach the IC 50 required for calpain inhibition, yet it exhibits no dose-limiting toxicities (DLTs) across broad population studies [3].

'(1S,2R)-Alicapistat (compound 22), administered intravenously (iv) or orally (po) at doses of 1-3 mg/kg, shows moderate plasma clearance rates (CLp) in mouse, rat, and dog (0.13-1.04 L/hr.kg) and higher rates in monkeys (1.98 L/hr.kg). The average steady-state volume of distribution (Vss) is moderate in mouse, dog, and monkey (0.64-1.8 L/kg), with rats displaying higher values (3.4 L/kg). The plasma elimination half-life (t 1/2) varies, being shortest in dogs (1.7 hours), 2.3 hours in monkeys, and approximately 6.0 hours in mice and rats. Oral bioavailability (F) is high in mice, rats, and dogs (>80%) but moderate in monkeys (14%) [2].'