Macdonald Dwight, Brideau Christine, Chan Chi Chung, Falgueyret Jean-Pierre, Frenette Richard, Guay Jocelyne, Hutchinson John H, Perrier Hélène, Prasit Peptiboon, Riendeau Denis, Tagari Philip, Thérien Michel, Young Robert N, Girard Yves
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy., Kirkland, Que., Canada H9H 3L1.
Bioorg Med Chem Lett. 2008 Mar 15;18(6):2023-7. doi: 10.1016/j.bmcl.2008.01.105. Epub 2008 Feb 2.
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).
本文描述了一系列新型5-脂氧合酶激活蛋白（FLAP）的取代2,2-双芳基双环庚烷抑制剂的发现及其构效关系（SAR）。构效关系研究表明，外芳基上的2,5-取代对活性最为有利。该系列中最有效的化合物具有一个邻位含氮芳基，通过亚甲基氧基作为5-取代基，以及一个极性基团如氨基甲酸酯作为2-取代基。所鉴定出的最有效化合物之一是5-苯并噻唑基甲氧基-2-吡啶基氨基甲酸酯衍生物2（FLAP IC(50)=2.8 nM），它在犬体内（静脉注射剂量为2.5μg/kg/min）可阻断89%的豚草诱导的尿液中白三烯E4（LTE(4)）生成。该化合物在人多形核（PMN）白细胞和人全血中均能抑制钙离子载体刺激的白三烯B4（LTB(4)）生成（IC(50)分别为2.0和33 nM）。
