Structure-activity relationships of the thienothiazine derivatives with their antiinflammatory, analgesic and ulcerogenic effects and their inhibitory effects on PGE2 biosynthesis

Abstract

A new series of thienothiazine derivatives were evaluated as a means of clarifying whether the changed chemical structure would have a different effect on carrageenin edema, scalded hyperalgesia and ulcerogenicity in rats and also have a different effect on PGE2 biosynthesis in vitro. The introduction of a Cl or CF3 group, but not an OH group, into position 6 of the thiophene ring resulted in an apparent increase in antiinflammatory and analgesic activity. A derivative with an OH or ester substituent in position 4 of the thiazine ring had a high pharmacological potential, but the introduction of other substituents such as ether and amide led to a significant loss in the activity. The pharmacological potential of two 5-hydroxy-2-aminopyridyl derivatives was less than what was achieved with various 2-aminopyridyl derivatives. Good correlations were observed between the lessening of the carrageenin edema and scalded hyperalgesia and inhibition of PGE2 biosynthesis. There was no statistically significant correlation between the ulcerogenicity and anti-inflammation or the ulcerogenicity and analgesia. As to the safety, tenoxicam, IIIc and IIIh showed relatively higher indices than those of others; and especially, tenoxicam was found to be a potent antiinflammatory drug with the highest safety index.