Asymmetric N-(3,3-diphenylpropyl)aminoalkyl esters of 4-aryl-2,6- dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acids with antihypertensive activity

Article abstract of DOI:10.1016/S0223-5234(98)80015-9

A series of asymmetric 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates characterized by the presence of a 3,3-diphenylpropylamino moiety in one of the ester groups were synthesized. They exhibited remarkable antihypertensive activity in spontaneously hypertensive rats as well as affinity for the 1,4- dihydropyridines binding site labelled by ³H-nitrendipine in the calcium channel. Introduction of this bulky and lipophilic amine confers to the whole series an elevated level of antihypertensive activity and a long duration of action, a structure-dependent modulation of the activity being found only in the subset characterized by the presence of a branched propylene bridge between the ester and the amino groups. The presence of the amino group is essential for oral activity. Out of this series, compound 9u (Rec 15/2375- lercanidipine) was selected for clinical development and obtained marketing authorization as an antihypertensive in several countries.