Title

Synthesis, screening and docking of small heterocycles as glycogen phosphorylase inhibitors

Date of this Version

1-1-2014

Document Type

Journal Article

Publication Details

Citation only

Schweiker, S. S., Loughlin, W. A., Lohning, A. S., Petersson, M. J., & Jenkins, I. D. (2014). Synthesis, screening and docking of small heterocycles as glycogen phosphorylase inhibitors. European Journal of Medicinal Chemistry, 84, 584-594.

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© Copyright, Elsevier Ltd, 2014

ISSN

0223-5234

Abstract

A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H- benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.1 mM-23.9 mM). A docking study using the crystal structure of human liver Glycogen Phosphorylase, provided insight into the interactions of heterocycles 5, 7, 9-13 and 19 with Glycogen Phosphorylase.

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This document has been peer reviewed.