Synthesis and antiinflammatory activity of 5-(1,6-dihydropyridyl)-tetrazol-2-acetic acids, esters and amides.
A series of 5-[3-(1,6-dihydropyridyl)]-2H-tetrazol-2-acetic acids (15-21), esters (7-14, 22-23) and amides (24-27) were synthesized in order to investigate the effect of alpha-substituents (R1 = H, Me) and 1,6-dihydropyridyl substituents (R2 = aryl, alkyl; R3 = phenoxy or amino) on antiinflammatory activity. Compounds having a R1 = H substituent generally exhibited greater activity. R2-aryl substituents showed higher potency except when R1 was Me in the acetic acid ester group of compounds. The relative potency order with respect to the R3-substituent was NH2 > PhO. When the R2-substituent was an aryl moiety, the effect of the R4-substituent on antiinflammatory activity was acid (R4 = OH) > or = ester (R4 = OMe), but when the R2-substituent was an alkyl group, the order of potency was generally ester > acid. Methyl 2-methyl-2-(5-[3-(6-i-butyl-1-phenoxycarbonyl-1,6-dihydropyridy l)]-2H- tetrazol-2-yl)acetate (13) was the most effective antiinflammatory agent in the group, reducing inflammation 93%, relative to ibuprofen's 52% inhibition, at 5 hr after a 100 mg/kg po dose.
Kumar
P
P
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Knaus
E E
EE
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004487:Edema / Q000188:drug therapy; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000085:Acetates; D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004095:Dihydropyridines; D004952:Esters; D013777:Tetrazoles