Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy

Gaofenngwe Nkomba; Gisella Terre'Blanche; Helena D Janse van Rensburg; Lesetja J Legoabe

doi:10.1007/s00044-022-02908-9

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A₁ receptors for the potential treatment of epilepsy

Med Chem Res. 2022;31(8):1277-1297. doi: 10.1007/s00044-022-02908-9. Epub 2022 May 24.

Authors

Gaofenngwe Nkomba¹, Gisella Terre'Blanche^{1

2}, Helena D Janse van Rensburg¹, Lesetja J Legoabe¹

Affiliations

¹ Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520 South Africa.
² Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520 South Africa.

Abstract

Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3-b]pyridine derivatives as non-nucleoside A₁ agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound 7c (thieno[2,3-b]pyridine derivative), displayed good binding affinity to the rA₁ AR (K _i = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives (6a-s) in relation to AR binding was also evaluated. A significant loss of activity against rA₁/rA_2A ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA₁ ARs (K _i < 10 nM) than rA_2A. Compound 6c had the best rA₁ affinity (K _i = 0.076 nM). Novel compounds (6d, 6k, 6l, 6m, 6n, 6o, 6p) were highly selective towards rA₁ AR (K _i between 0.179 and 21.0 nM). Based on their high selectivity for A₁ ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations. A decrease in rA₁ AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines (7a, 7d, 7c) from amino-3,5-dicyanopyridine derivatives (6a, 6f, 6g).

Keywords: Adenosine A1/A2A receptors; Amino-3,5-dicyanopyridines; Epilepsy; Intramolecular cyclisation; Thieno[2,3-b]pyridines.