Calcium channel blocking and positive inotropic activities of ethyl 5-cyano-1,4-dihydro-6-methyl-2-[(phenylsulfonyl)methyl]-4-aryl-3- pyridine-carboxylate and analogues. Synthesis and structure-activity relationships.
The synthesis and pharmacological evaluation of a series of 2-[(arylsulfonyl)methyl]-4-aryl-5-cyano-1,4-dihydropyridine-3-carboxylic acid esters and analogues are described. These compounds possess a unique profile namely, calcium channel blocking and positive inotropic activities in vitro. Compound 54 was selected as the best compound in the series and was studied in detail. The synthesis and biological profiles of enantiomers of 54 are also reported. The data indicate that although the calcium channel blocking property of 54 is stereospecific the positive inotropic activity is not. Examples of 3- and 6-cyano and other closely related 1,4-dihydropyridine derivatives are described and evaluated for comparison and were found to be devoid of dual activities mentioned above.
Sircar
I
I
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Gregor
E K
EK
Anderson
K R
KR
Haleen
S J
SJ
Shih
Y H
YH
Weishaar
R E
RE
Steffen
R P
RP
Pugsley
T A
TA
Taylor
M D
MD
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002264:Carboxylic Acids; D004095:Dihydropyridines; D009539:Nicotinic Acids; D009570:Nitriles; D013450:Sulfones