Long-acting dihydropyridine calcium antagonists. 3. Synthesis and structure-activity relationships for a series of 2-[(heterocyclylmethoxy)methyl] derivatives.
The preparation of 1,4-dihydropyridines containing (heterocyclylmethoxy)methyl groups in the 2-position is described and the structural identification of certain of the compounds using 1H NMR spectroscopic methods is reported. The calcium antagonist activity of the compounds on rat aorta is listed and is compared with the negative inotropic potency as determined by using a Langendorff-perfused guinea pig heart model. Several compounds are more potent than nifedipine and show greater selectivity for the vasculature over the heart. One compound, 2-[(2-amino-4-hydroxypyrimidin-6-yl)methoxy]-4- (2,3-dichlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl- 1,4-dihydropyridine (27, UK-56,593), was identified as a potent (IC50 = 1.6 x 10(-9) M), tissue-selective calcium antagonist which proved to have a markedly longer duration of action (greater than 4.5 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; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007202:Indicators and Reagents; D011188:Potassium; D002118:Calcium