Long-acting dihydropyridine calcium antagonists. 4. Synthesis and structure-activity relationships for a series of basic and nonbasic derivatives of 2-[(2-aminoethoxy)methyl]-1,4-dihydropyridine calcium antagonists.
The preparation of a series of 1,4-dihydropyridines (DHPs) which have polar, acyclic, nonbasic substituents on an ethoxymethyl chain at the 2-position is described. In addition, in order to assess the effects of incorporating a basic center into DHPs of this type, a series of glycinamides were also prepared. The calcium antagonist activity on rat aorta of both these classes of DHP is compared with their negative inotropic activity as determined by using a Langendorff perfused guinea pig heart model. A number of the compounds evaluated have activity of the same order as nifedipine although those with more extended substituents have lower potency, particularly when a basic substituent is present. The compounds examined displayed a wide variation in selectivity for vascular over cardiac tissue. A number of structure-activity relationship trends were identified and possible explanations to account for the differences in selectivity observed are advanced. One of the compounds, 2-[[2-[[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6- methyl-1,4-dihydropyrid-2-yl]methoxy]ethyl]amino]acetamide (26, UK-51,656), was identified as a potent (IC50 = 4 x 10(-9) M) calcium antagonist which is 20-fold selective for vascular over cardiac tissue and which has a markedly longer duration of action (greater than 5 h) than nifedipine in the anesthetized dog on intravenous administration. The pharmacokinetic half-life of 26 was established as 4.7 h and possible explanations are advanced to account for 26 having a shorter plasma half-life than amlodipine and a longer plasma half-life than felodipine.
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* / Q000493:pharmacokinetics / Q000494:pharmacology; D015220:Calcium Channels; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014665:Vasodilator Agents
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D011978:Receptors, Nicotinic; D014665:Vasodilator Agents