Alicapistat

Alicapistat (ABT-957) is an orally active selective inhibitor of human calpains 1 and 2 for the potential application of Alzheimer's disease (AD)^[1]. Alicapistat mitigates the metabolic liability of carbonyl reduction and inhibits calpain 1 with an IC₅₀ value of 395 nM^[2]. IC50 & Target: IC50: 395 nM (Human calpains 1)^[2]. In Vitro: Alicapistat exihibits inadequate CNS-penetration concentrations to obtain a pharmacodynamic effect^[1].
Calpain 1 (µ-calpain) and 2 (m-calpain) expression in a calcium-dependent manner with µ-molar or m-molar calcium concentrations required for their respective activation, respectively. Alicapistat (compound 22) (100 nM) prevents Aβ oligomer-induced deficits in synaptic transmission in rat^[2].
Alicapistat (compound 22) (385 nM) displays efficacy with respect to prevention of NMDA-induced neurodegeneration and A-induced synaptic dysfunction in rat hippocampal slice cultures^[2].
Alicapistat (9-21 nM) has the CSF concentrations without reaching the IC₅₀ for calpain inhibition and shows no dose-limiting toxicities (DLTs) in the broad populations studies^[3]. In Vivo: Alicapistat (compound 22) (iv or po; 1-3 mg/kg) shows moderate mean plasma clearance values (CLp) in mouse, rat, and dog (0.13-1.04 L/hr.kg), while high in monkey (1.98 L/hr.kg). Mean steady-state volume of distribution values (Vss) were moderate in mouse, dog, and monkey (0.64-1.8 L/kg), but higher in rat (3.4 L/kg). The plasma elimination half-life (t_1/2) was shortest in dog (1.7 hours), followed by 2.3 hours in monkey and approximately 6.0 hours in mouse and rat. Oral bioavailability (F) values were high in mouse, rat, and dog (>80%), while moderate in monkey (14%)^[2].