Synthesis and antiinflammatory activity of 2H-tetrazol-2-acetic acids, esters and amides.
A series of 5-(pyridyl)-2H-tetrazol-2-acetic acids (16-21), esters (10-15), and amides (22-27) was synthesized in order to investigate the effect of 5-substituents (R1 = 2-, 3- or 4-pyridyl) and alpha-substituents (R2 = H, Me) on anti-inflammatory activity. The point of attachment of the R1-pyridyl substituent influenced potency. The relative potencies in the acetic acid ester, acetic acid and acetamide classes of compounds were 2- and 4- greater than 3-pyr, 2- and 3- greater than 4-pyr, and 4- greater than 2- and 3-pyr, respectively. In the acetic acid ester and acetamide classes, compounds having a R2 hydrogen substituent were generally more potent than corresponding methyl substituted compounds, whereas, in the acetic acid class the reverse applied. The relative order of anti-inflammatory potency was generally amide greater than ester greater than acid. 2-[5-(4-Pyridyl)-2H-tetrazol-2-yl]acetamide (26) was the most effective antiinflammatory agent in the series, reducing inflammation by 53% at 3 and 5 hr after a 25 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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D000081:Acetamides / Q000138:chemical synthesis / Q000494:pharmacology; D000085:Acetates / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry; D002351:Carrageenan; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D000081:Acetamides; D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011725:Pyridines; D013777:Tetrazoles; D002351:Carrageenan