Synthesis and hypoglycemic activity of S-acyl derivatives of 3-mercaptopicolinic acid

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Abstract
A series of S-alkanoyl and benzoyl derivatives of 3-mercaptopicolinic acid (3-MPA) was prepared and studied for hypoglycemic activity [in fasted rats]. Three alkanoyl derivatives (propionyl, pivaloyl and 1-adamantanecarbonyl, 19-21) were prepared with increasing bulk around the thio ester bond. The benzoyl derivatives contained aromatic substituents chosen from a .sigma.-.pi. cluster chart so that the esters prepared had a wide range of electronic and solubility properties. Compounds with substituents which increased lipid solubility [p-chlorobenzoyl (4), p-trifluoromethylbenzoyl (6) and pivaloyl (20)] had the greatest potency at a dose of 300 mg/kg. Hydrolysis rates, measured at pH 6 and 8, indicated that in vivo breakdown to 3-MPA probably did not account for the observed hypoglycemic activity of the esters. Esters 4, 6 and 20 were less potent than 3-MPA in comparative dose range studies.

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