Synthesis, screening and docking of small heterocycles as Glycogen Phosphorylase inhibitors

• New heterocyclic inhibitors of Glycogen Phosphorylase a, with IC50 25μM < 7.8 mM.
• Rule of three, and predicted Log P and Log S within limits for compounds 5, 7, 11–13.
• In silico docking of 5, 7, 9–13, 19 gave insight at AMP, indole, and purine sites.
• Some preference for purine site binding; for example tetrahydropyrimidine 11.
• Thiazoline 7 was a key hit that inhibited GPa, with an appropriate LE and LELP.

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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