Lead discovery and synthesis of selective T-type calcium channel blockers

T-type calcium channels belong to the family of voltage-gated calcium channels (VGCCs). The electrophysiological features of the T-channels are well established: low-voltage activated calcium current, fast inactivation kinetics and low unitary conductance. Calcium enters through T-channels and mediates membrane depolarisation and increases intracellular calcium concentration that are thought to contribute significantly to pacemaker activities in the heart and in neurons, hormone secretion, epilepsy and pain. Though their presence in many tissues and their potential implication in various disease states, low-voltage activated T-type calcium channels have only recently become targets of interest. Unfortunately, the lack of selective T-channel blockers has hampered further characterisation of these channels. Selective inhibition of T-channels may have clinical importance in cardiovascular diseases and some forms of epilepsy and pain.1 This work focuses on novel research approaches to discover potent and selective T-channel modulators. These molecules may be potential drugs for treating human diseases, as well as important tools to understand the physiological role of these channels. A 1,4-dihydropyridine scaffold with a potential selective inhibition activity of T-type calcium channels was drawn using molecular modeling techniques. In particular computing alignment-free molecular descriptors, also called GRid-INdependent descriptors or GRIND, were used to obtain a model able to predict T-type calcium channel activity and to test potential hERG toxicity based on a model developed in our laboratory.2 The N-substituted 1,4-dihydropyridines were synthetised by a microwave assisted multi-component reaction catalyzed by L-Proline.