NOVEL DUAL INHIBITORS OF 5-LIPOXYGENASE AND THROMBOXANE A(2) SYNTHETASE - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 3-PYRIDYLMETHYL-SUBSTITUTED 2-AMINO-6-HYDROXYBENZOTHIAZOLE DERIVATIVES

As part of our search for novel antiinflammatory drug candidates, we h ave designed and synthesized a series of 3-pyridylmethyl-substituted 2 -amino-6-hydroxybenzothiazoles. Introduction of a 3-pyridylmethyl grou p into the 2-amino group (type-A) or the benzene ring (type-B) of 2-am ino-6-hydroxybenzothiazoles imparted dual inhibitory activity against the production by glycogen-induced peritoneal cells of rat (in vitro) of leukotriene B-4 (LTB(4)) and thromboxane A(2) (TXA(2)), while not s ignificantly inhibiting that of prostaglandin E(2) (PGE(2)). The obser ved inhibition of the former two arachidonic acid metabolites was indi cated to be the result of a direct action on 5-Lipoxygenase and TXA(2) synthetase by a cell-free in vitro assay. On the other hand, the inhi bitory activities against PGE(2) production were for most compounds ve ry weak, indicating that they did not inhibit cyclooxygenase. Structur e-activity relationship studies concerning the position of the 3-pyrid ylmethyl group revealed that type-B compounds generally showed about 1 0-fold stronger inhibitory activity against TXA(2) synthetase than typ e-A compounds. The position of the 3-pyridylmethyl group played an imp ortant role in TXA(2) synthetase inhibition. When some of these compou nds (8, 13a, 26a (E3040), 26b, 27b, and 28b) were orally administered in the rat TNB/ethanol-induced chronic colitis model (100 mg/ kg), the production of both LTB(4) and TXB(2) in the rat colon was reduced (ex vivo). In addition, one type-B compound, 6-hydroxy-5,7-dimethyl-2-(me thylamino)-4 zole (26a), demonstrated a therapeutic effect at treatmen ts of 100 mg/kg po once daily for 11 days and showed almost comparable activity to sulfasalazine at a dose of 500 mg/kg, the reference drug for inflammatory bowel diseases, in this in vivo model.