Synthesis and hypoglycemic activity of 4-substituted 3-mercaptopicolinic acids.

3-Mercapto-4-methylpicolinic acid one of very few compounds derived from 3-mercaptopicolinic acid (3-MPA) to have hypoglycemic activity. In an effort to find compounds with greater potency than 3-MPA, several 4-substituted 3-mercaptopicolinic acids (4-OMe, OC6H5, SMe, SH, Cl, NH2, Et; 1-7) were prepared and tested in 48-h fasted rats. None was hypoglycemic in this test system after oral dosing of 150 mg/kg.

Mercapto heterocyclic carboxylic acids, analogues of 3-mercaptopicolinic acid.

3-Mercaptopicolinic acid (3-MPA), a potent hypoglycemic agent in fasted rats, provided the impetus for substituting this compound with a 5-mercapto group (1), a 6-carboxyl group (2), and a 5-mercapto and 6-carboxyl group (3) and for replacing the pyridine ring with other heterocycles: quinoline (4), thiazole (5), pyrazine (6), isoquinoline (7), and indole (8). The methyl sulfoxide (9) and sulfone (10) of 3-MPA were also prepared. The new compounds 1-10, with the exception of 8, did not lower blood glucose levels in 48-h fasted rats.

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

A series of S-alkanoyl and benzoyl derivatives of 3-mercaptopicolinic acid (3-MPA) was prepared and studied for hypoglycemic activity. 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.

Synthesis and hypoglycemic activity of phenacyltriphenylphosphoranes and phosphonium salts.

Phenacyl-riphenylphosphorane (1a) and several analogs substituted in the meta position of the phenacyl group lowered blood glucose levels in 48-hr fasted rats. The corresponding phosphonium salts had comparable hypoglycemic activity. Two compounds (1a and 1b) were also hypoglycemic in fed rats, but hypoglycemia could not be elicited in another species.