title: 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 complete removal of cathepsin inhibitory properties as compared to PADK. Isomers of the lead compound SD1002 were synthesized, and the modulatory activity was determined to be stereoselective. In addition, the lead compound was tested in transgenic mice with results indicating protection against AD-type protein accumulation pathology.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States.
authors.forename: Kishore
authors.initials: K
authors.lastname: Viswanathan
authors.affiliation: Synaptic Dynamics Inc. , Farmington, Connecticut 06032, United States.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Hoover
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States ; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke , Pembroke, North Carolina 28372, United States.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Hwang
authors.affiliation: William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke , Pembroke, North Carolina 28372, United States.
authors.forename: Meagan L
authors.initials: ML
authors.lastname: Wisniewski
authors.affiliation: William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke , Pembroke, North Carolina 28372, United States.
authors.forename: Uzoma S
authors.initials: US
authors.lastname: Ikonne
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States ; William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina-Pembroke , Pembroke, North Carolina 28372, United States.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Bahr
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut , Storrs, Connecticut 06269, United States ; Synaptic Dynamics Inc. , Farmington, Connecticut 06032, United States.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Wright
keywords: Alzheimer's disease; PADK; cathepsin B; lysosomal modulator; nonpeptidic inhibitors