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-1-[2-[[4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5- (methoxycarbonyl)-6-methyl-1,4-dihydropyrid-2-yl]methoxy]ethyl]-4( 3H)- imidazolone (20b, UK-55,444), was identified as a potent (IC50 = 8 x 10(-9) M) calcium antagonist which is 40-fold selective for vascular over cardiac tissue and which has a significantly longer duration of action (greater than 3 h) than nifedipine in the anesthetized dog on intravenous administration.
Alker
D
D
Pfizer Central Research, Sandwich, Kent, United Kingdom.
Campbell
S F
SF
Cross
P E
PE
Burges
R A
RA
Carter
A J
AJ
Gardiner
D G
DG
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology*; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D004285:Dogs; D006168:Guinea Pigs; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular; D009206:Myocardium; D009928:Organ Specificity; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007093:Imidazoles; C064293:UK 55444