Mitigating the Metabolic Liability of Carbonyl Reduction: Novel Calpain Inhibitors with P1' Extension.

ABSTRACT: Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1H)-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays. Using cytosolic clearance as a tailored in vitro ADME assay coupled with in vitro hepatocyte metabolism enabled the identification of analogues with enhanced stability ag

SUBMITTER: Kling A 

PROVIDER: S-EPMC5846052 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature