Nonpeptidic lysosomal modulators derived from z-phe-ala-diazomethylketone for treating protein accumulation diseases.

ABSTRACT: Lysosomes are involved in protein turnover and removing misfolded species, and their enzymes have the potential to offset the defect in proteolytic clearance that contributes to the age-related dementia Alzheimer's disease (AD). The weak cathepsin B and L inhibitor Z-Phe-Ala-diazomethylketone (PADK) enhances lysosomal cathepsin levels at low concentrations, thereby eliciting protective clearance of PHF-τ and Aβ42 in the hippocampus and other brain regions. Here, a class of positive modulators is established with compounds decoupled from the cathepsin inhibitory properties. We utilized PADK as a departure point to develop nonpeptidic structures with the hydroxyethyl isostere. The first-in-class modulators SD1002 and SD1003 exhibit improved levels of cathepsin up-regulation but almost comple

SUBMITTER: Viswanathan K 

PROVIDER: S-EPMC4025860 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature