Synthesis and anti-inflammatory activity of 5-(1,4-dihydropyridyl)-tetrazol-2-acetic acids, esters and amides.
Thirteen 5-[3-(1,4-dihydropyridyl)]-2H-tetrazol-2-acetic acids (18-30), seventeen esters (4-17, 32, 35, 41) and eight amides (31, 32-34, 36-40) were synthesized in order to investigate the effect of alpha-substituents (R1 = H, Me) and 1,4-dihydropyridyl substituents (R2 = aryl, alkyl; R3 = phenoxy, methoxy or amino) on anti-inflammatory activity. The effects of the R1, R2 or R3-substituents were variable but highly interdependent. The relative order of anti-inflammatory potency was generally acid greater than amide and ester. Methyl 2-methyl-2-(5-[3-(4-phenyl-1-carbamoyl-1,4-dihydropyridyl)]-2H- tetrazol-2-yl) acetate (35) was the most effective anti-inflammatory agent in the group, reducing inflammation 96% at 5 hr after a 50 mg/kg po dose, relative to ibuprofen's 52% inhibition at 5 hr after a 100 mg/kg po dose.
Kumar
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Knaus
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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*; D002351:Carrageenan; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis; 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; D011355:Prodrugs; D013777:Tetrazoles; D002351:Carrageenan