4-aryl -1,4-dihydropyridines exemplified by amlodipine are used world wide for the treatment of hypertension. We have for a number of years been interested in bioisosteric replacement of the 4-aryl group with an isoxazole ring. For the 4’-isoxazole to 4-dihydropyridine connection, the 4-isoxazole has no para position, and the π-deficient isoxazole  ring serves the function of electron withdrawing groups on the carbocyclic  4-aryl ring.  Substitution on the 3- and 5–position of the isoxazole serves to explore novel conformational and configurational space. We recently have expanded our study to new analogs, which were constructed with our recently developed lanthanide catalysis, which produces better yields in the face of significant steric hindrance. We observed that the new analogs, which represent new composition of matter, possess robust activity at the voltage gated calcium channel, and exhibit sub-type selectivity. The efficacy is improved over our previous work. Our working hypothesis for drug-receptor binding is based on a homology model using  the recently reported cryo-EM  coordinates the rabbit Cav1.1- nifedipine complex of Zhao, <i>et al</i> (<i>Cell</i>, 2019, pdb accession number 6JP5). Not only does the new homology model explain our current data, but also explains several of our other observations that had not been adequately understood in terms of  previous homology modeling.

Isoxazolyl dihydropyridines exhibit sub-type selective voltage gated calcium channel antagonism

ACS Fall 2021

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