SUBSTITUTED THIOPYRANO[2,3,4-C,D]INDOLES AS POTENT, SELECTIVE, AND ORALLY-ACTIVE INHIBITORS OF 5-LIPOXYGENASE - SYNTHESIS AND BIOLOGICAL EVALUATION OF L-691,816

Thiopyrano[2,3,4-c,d]indoles are a new class of 5-lipoxygenase (5-LO) inhibitors. SAR studies have demonstrated that the thiopyran ring, the 5-phenylpyridine substituent, and an acidic functional group on a fou r-carbon C-2 side chain are all required for optimal inhibitor potency . In contrast, the indolic nitrogen may be substituted with a variety of lipophilic groups. As a result of the SAR investigation, 44 (L-691, 816; -c,d]indol-2-yl]-2,2-dimethylpropyl]-1H-tetrazole) has been ident ified as a potent inhibitor of the 5-LO reaction both in vitro and in a range of in vivo models. Compound 44 inhibits 5-HPETE production by both rat and human 5-LO and LTB4 synthesis in human PMN leukocytes (IC 50s 16,75, and 10 nM, respectively). The mechanism of inhibition of 5- LO activity by compound 44 appears to involve the formation of a rever sible deadend complex with the enzyme and does not involve reduction o f the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO w hen compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active i n a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pret reatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg;2-h pretreatment). Excellent functional act ivity was also observed in both the conscious allergic monkey and shee p models of asthma. In the latter case, the functional activity observ ed correlated with the inhibition of urinary LTE4 excretion.