LONG-ACTING DIHYDROPYRIDINE CALCIUM-ANTAGONISTS .5. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS FOR A SERIES OF 2-[[(N-SUBSTITUTED-HETEROCYCLYL)ETHOXY]METHYL]-1,4-DIHYDROPYRIDINE CALCIUM-ANTAGONISTS

The synthesis of a series of 1,4-dihydropyridines which have N-linked heterocycles at the terminus of an ethoxymethyl chain at the 2-position is described. The calcium antagonist activity on rat aorta of this class of DHPs is compared with their negative inotropic activity as determined by using a Langendorff-perfused guinea pig heart model. The compounds examined show a wide range of selectivity for vascular over cardiac tissue, with those analogues which possess an amide group at the terminus of the 2-substituent proving the most selective. From the in vitro data obtained for a series of 1,2,3-triazoles, it is possible to conclude that the SARs for binding to the calcium channels in vascular and cardiac tissue are different. One of the compounds, 2-amino-l-[2-[[4-(2,3-dichIorophenyl)-3-(eth-oxycarbonyl)-5-(methoxycarbonyl)-6-methyl-l,4-dihydropyrid-2-yl]methoxy]ethyl]-4(3tf)-imidazolone (20b, UK-55,444), was identified as a potent (IC50 = 8 x 10-9M) calcium antagonist which is 40-fold selective for vascular over cardiac tissue and which has a significantly longer duration of action (>3 h) than nifedipine in the anesthetized dog on intravenous administration. © 1990, American Chemical Society. All rights reserved.