Discovery of Aryl Aminothiazole γ-secretase Modulators with Novel Effects on Amyloid β-peptide Production

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2021 Nov 12

PMID 34767913

Citations 3

Authors

Sanjay Bhattarai

Lei Liu

Michael S Wolfe

Affiliations

Soon will be listed here.

Abstract

A series of analogs based on a prototype aryl aminothiazole γ-secretase modulator (GSM) were synthesized and tested for their effects on the profile of 37-to-42-residue amyloid β-peptides (Aβ), generated through processive proteolysis of precursor protein substrate by γ-secretase. Certain substitutions on the terminal aryl D ring resulted in an altered profile of Aβ production compared to that seen with the parent molecule. Small structural changes led to concentration-dependent increases in Aβ37 and Aβ38 production without parallel decreases in their precursors Aβ40 and Aβ42, respectively. The new compounds therefore apparently also stimulate carboxypeptidase trimming of Aβ peptides ≥ 43 residues, providing novel chemical tools for mechanistic studies of processive proteolysis by γ-secretase.

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