As part of our search for novel antiinflammatory
drug candidates, we have designed and synthesized a series of 3-pyridylmethyl-substituted 2-amino-6- hydroxybenzothiazoles. Introduction of a 3-pyridylmethyl group into the 2-amino group (type-A) or the
benzene ring (type-B) of 2-amino-6-hydroxybenzothiazoles imparted dual inhibitory activity against the production by
glycogen-induced peritoneal cells of rat (in vitro) of
leukotriene B4 (
LTB4) and
thromboxane A2 (TXA2), while not significantly inhibiting that of
prostaglandin E2 (
PGE2). The observed inhibition of the former two
arachidonic acid metabolites was indicated to be the result of a direct action on
5-lipoxygenase and TXA2
synthetase by a cell-free in vitro assay. On the other hand, the inhibitory activities against
PGE2 production were for most compounds very weak, indicating that they did not inhibit
cyclooxygenase. Structure-activity relationship studies concerning the position of the 3-pyridylmethyl group revealed that type-B compounds generally showed about 10-fold stronger inhibitory activity against TXA2
synthetase than type-A compounds. The position of the 3-pyridylmethyl group played an important role in TXA2
synthetase inhibition. When some of these compounds (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
LTB4 and TXB2 in the rat colon was reduced (ex vivo). In addition, one type-B compound, 6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole (26a), demonstrated a
therapeutic effect at treatments 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.