7 - N- and C-Glycopyranosyl heterocycles as glycogen phosphorylase inhibitors

Abstract

Glycogen phosphorylase (GP), the main regulatory enzyme of glycogen degradation directly controlling blood sugar levels, is a validated target in seeking new therapies against type 2 diabetes mellitus. Several compounds inhibiting GP diminish serum glucose levels and exert beneficial effects in other diseases. The most intensively investigated GP inhibitors are derivatives of glucose. Nanomolar inhibitors were discovered amidst N-glucopyranosyl ureas, glucopyranosylidene-spiro-heterocycles, and N- and C-glucopyranosyl heterocycles, the latter two making the subject of this survey. A systematic presentation of synthetic methods categorized by ring size and constitution for both types of glucosyl heterocycles and their annulated derivatives is followed by compounds with modified sugar units. The GP inhibitory properties are discussed along with tabular presentation of data. Beside in vitro studies, a growing body of ex vivo and in vivo investigations of glucose-derived GP inhibitors show promise to apply such compounds as drug development candidates.