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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.

Publication ,  Journal Article
Hutchinson, JH; Riendeau, D; Brideau, C; Chan, C; Delorme, D; Denis, D; Falgueyret, JP; Fortin, R; Guay, J; Hamel, P
Published in: Journal of medicinal chemistry
September 1993

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 four-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; 5-[3-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy ]- 4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpro pyl]-1H- tetrazole) has been identified 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 (IC50s 16, 75, and 10 nM, respectively). The mechanism of inhibition of 5-LO activity by compound 44 appears to involve the formation of a reversible deadend complex with the enzyme and does not involve reduction of the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO when compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active in a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pretreatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg; 2-h pretreatment). Excellent functional activity was also observed in both the conscious allergic monkey and sheep models of asthma. In the latter case, the functional activity observed correlated with the inhibition of urinary LTE4 excretion.

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Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

September 1993

Volume

36

Issue

19

Start / End Page

2771 / 2787

Related Subject Headings

  • Structure-Activity Relationship
  • Sheep
  • Saimiri
  • Rats, Sprague-Dawley
  • Rats
  • Pyridines
  • Neutrophils
  • Medicinal & Biomolecular Chemistry
  • Male
  • Lipoxygenase Inhibitors
 

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Hutchinson, J. H., Riendeau, D., Brideau, C., Chan, C., Delorme, D., Denis, D., … Hamel, P. (1993). 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. Journal of Medicinal Chemistry, 36(19), 2771–2787. https://doi.org/10.1021/jm00071a008
Hutchinson, J. H., D. Riendeau, C. Brideau, C. Chan, D. Delorme, D. Denis, J. P. Falgueyret, R. Fortin, J. Guay, and P. Hamel. “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.Journal of Medicinal Chemistry 36, no. 19 (September 1993): 2771–87. https://doi.org/10.1021/jm00071a008.
Hutchinson JH, Riendeau D, Brideau C, Chan C, Delorme D, Denis D, et al. 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. Journal of medicinal chemistry. 1993 Sep;36(19):2771–87.
Hutchinson, J. H., et al. “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.Journal of Medicinal Chemistry, vol. 36, no. 19, Sept. 1993, pp. 2771–87. Epmc, doi:10.1021/jm00071a008.
Hutchinson JH, Riendeau D, Brideau C, Chan C, Delorme D, Denis D, Falgueyret JP, Fortin R, Guay J, Hamel P. 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. Journal of medicinal chemistry. 1993 Sep;36(19):2771–2787.
Journal cover image

Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

September 1993

Volume

36

Issue

19

Start / End Page

2771 / 2787

Related Subject Headings

  • Structure-Activity Relationship
  • Sheep
  • Saimiri
  • Rats, Sprague-Dawley
  • Rats
  • Pyridines
  • Neutrophils
  • Medicinal & Biomolecular Chemistry
  • Male
  • Lipoxygenase Inhibitors