Thiopyrano[2,3,4-cd]indoles as 5-lipoxygenase inhibitors: Synthesis, biological profile, and resolution of 2-[2-[1-(4-chlorobenzyl)-4-methyl-6- [(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2- yl]ethoxy]butanoic acid

Article abstract of DOI:10.1021/jm00034a013

Leukotriene biosynthesis inhibitors have potential as new therapies for asthma and inflammatory diseases. The recently disclosed thiopyrano[2,3,4- cd]indole class of 5-lipoxygenase (5-LO) inhibitors has been investigated with particular emphasis on the side chain bearing the acidic functionality. The SAR studies have shown that the inclusion of a heteroatom (O or S) in conjunction with an α-ethyl substituted acid leads to inhibitors of improved potency. The most potent inhibitor prepared contains a 2-ethoxybutanoic acid side chain. This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5- phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2- yl]ethoxy]butanoic acid, L-699,333), inhibits 5-HPETE production by human 5- LO and LTB₄ biosynthesis by human PMN leukocytes and human whole blood (IC₅₀s of 22 nM, 7 nM and 3.8 μM, respectively). The racemic acid 14d has been shown to be functionally active in a rat pleurisy model (inhibition of LTB₄, ED₅₀ = 0.65 mg/kg, 6 h pretreatment) and in the hyperreactive rat model of antigen-induced dyspnea (50% inhibition at 2 and 4 h pretreatment; 0.5 mg/kg po). In addition, 14d shows excellent functional activity against antigen-induced bronchoconstriction in the conscious squirrel monkey [89% inhibition of the increase in R(L) and 68% inhibition in the decrease in C(dyn) (0.1 mg/kg, n = 3)] and in the conscious sheep models of asthma (iv infusion at 2.5 μg/kg/min). Acid 14d is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of human 15-LO, porcine 12-LO and ram seminal vesicle cyclooxygenase (IC₅₀ > 5 μM) or competition in a FLAP binding assay (IC₅₀ > 10 μM). Resolution of 14d affords 14g, the most potent diastereomer, which inhibits the 5-HPETE production of human 5-LO and LTB₄ biosynthesis of human PMN leukocytes and human whole blood with IC₅₀s of 8 nM, 4 nM, and 1 μM respectively. The in vitro and in vivo profile of 14d is comparable to that of MK-0591, which has showed biochemical efficacy in inhibiting ex vivo LTB₄ biosynthesis and urinary LTE₄ excretion in clinical trials.