Long acting dihydropyridine calcium antagonists. 2. 2-[2-Aminoheterocycloethoxy]methyl derivatives.
A series of [(2-aminoheterocycloethoxy)methyl]dihydropyridines were prepared as selective coronary vasodilators. Results showed that a wide variety of five- and six-membered heterocycles were acceptable at the 2-position of the dihydropyridine ring and in vitro potency and tissue selectivity was independent of the basicity of these heterocycles. The SAR indicated that activity was optimum when the largest ester group was placed at the 3 rather than 5 position. 2-[[2-[(3-Amino-1H-1,2,4-triazol-5-yl)amino]ethoxy]methyl]-4- (2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl- 1,4-dihydropyridine (3b) (UK-52,831) emerged as a potent (IC50 = 6.3 X 10(-9) M) and tissue-selective calcium channel blocker with a duration of action greater than 7 h in the anaesthetized dog.
Arrowsmith
J E
JE
Pfizer Central Research, Sandwich, Kent, United Kingdom.
Campbell
S F
SF
Cross
P E
PE
Burges
R A
RA
Gardiner
D G
DG
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014665:Vasodilator Agents