Evaluation of novel Hyphodermin derivatives as Glycogen Phosphorylase a inhibitors

Abstract

The lipophilicity, permeability, solubility, polar surface area and 'rule-of-five' properties were assessed, using QikProp v2.5 (Schr椩nger, Inc.) and ALOGPS 2.1 calculations, for 25 Hyphodermin derivatives. These compounds obeyed the 'rule of five', and the calculated physicochemical values were generally within desired limits. All compounds were tested against Glycogen Phosphorylase a (GPa). Four phenyl and benzyl substituted 2-oxo-hexahydro and tetrahydrobenzo[cd]indole carboxylic acids were identified as novel inhibitors of GPa with estimated IC50 values in the range 0.8-1.3 mM. Molecular modeling of these novel inhibitors was used to obtain the main structural features of this class of molecule for future structure-activity relationship studies.