Substituted 2,2-bisaryl-bicycloheptanes as novel and potent inhibitors of 5-lipoxygenase activating protein.

Journal Article (Journal Article)

The discovery and SAR of a novel series of substituted 2,2-bisaryl-bicycloheptane inhibitors of 5-lipoxygenase activating protein (FLAP) are herein described. SAR studies have shown that 2,5-substitution on the exo-aryl group is optimal for potency. The most potent compounds in this series have an ortho-nitrogen aryl linked with a methyleneoxy as the 5-substituent and a polar group such as a urethane as the 2-substituent. One of the most potent compounds identified is the 5-benzothiazolymethoxy-2-pyridinylcarbamate derivative 2 (FLAP IC(50)=2.8 nM) which blocks 89% of ragweed induced urinary LTE(4) production in dogs (at an I.V. dose of 2.5 microg/kg/min). This compound inhibits calcium ionophore stimulated LTB(4) production in both human polymorphonuclear (PMN) leukocytes and human whole blood (IC(50)=2.0 and 33 nM, respectively).

Full Text

Duke Authors

Cited Authors

  • Macdonald, D; Brideau, C; Chan, CC; Falgueyret, J-P; Frenette, R; Guay, J; Hutchinson, JH; Perrier, H; Prasit, P; Riendeau, D; Tagari, P; Thérien, M; Young, RN; Girard, Y

Published Date

  • March 2008

Published In

Volume / Issue

  • 18 / 6

Start / End Page

  • 2023 - 2027

PubMed ID

  • 18276139

Electronic International Standard Serial Number (EISSN)

  • 1464-3405

International Standard Serial Number (ISSN)

  • 0960-894X

Digital Object Identifier (DOI)

  • 10.1016/j.bmcl.2008.01.105


  • eng