THE DEVELOPMENT OF A NOVEL SERIES OF (QUINOLIN-2-YLMETHOXY)PHENYL-CONTAINING COMPOUNDS AS HIGH-AFFINITY LEUKOTRIENE RECEPTOR ANTAGONISTS .3. STRUCTURAL VARIATION OF THE ACIDIC SIDE-CHAIN TO GIVE ANTAGONISTS OF ENHANCED POTENCY
THE DEVELOPMENT OF A NOVEL SERIES OF (QUINOLIN-2-YLMETHOXY)PHENYL-CONTAINING COMPOUNDS AS HIGH-AFFINITY LEUKOTRIENE RECEPTOR ANTAGONISTS .3. STRUCTURAL VARIATION OF THE ACIDIC SIDE-CHAIN TO GIVE ANTAGONISTS OF ENHANCED POTENCY
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DOI：
10.1021/jm00172a024
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发表时间：
1990-10-01
影响因子：
7.3
通讯作者：
VANINWEGEN, RG
中科院分区：
文献类型：
--
作者：
GALEMMO, RA;JOHNSON, WH;VANINWEGEN, RG
本文是系列概述含有（喹啉-2-基甲氧基）苯基部分的口服活性磺胺肽白三烯拮抗剂的发展的第三篇。在这项工作中，酸侧链取代基的系统变化导致了这些化合物口服活性的戏剧性和可重复的变化，可能是由于它们的药代动力学性质的改变。最有效的化合物是5-[4-[4-（喹啉-2-基甲氧基）苯基]-3-甲基丁基]四唑（32），它具有良好的体外拮抗剂活性，口服效力比目前的临床候选药物提高了3-10倍。这些优化研究的新发现如下：在酸侧链上的氧取代对拮抗剂活性不是必需的，在体外和体内的活性可以通过在. γ上的烷基或苯基取代而增强。对取代的（喹啉-2-基甲氧基）苯基衍生物的酸侧链上的-碳原子，并且（喹啉-2-基甲氧基）苯基环相邻侧链碳原子的自由旋转需要活性。本报告的先导化合物（32）是从豚鼠肺中纯化的[3H]LTD4结合受体膜的竞争性抑制剂（Ki = 12 .+-）。3 nM)，观察豚鼠肺条LTC4、LTD4、LTE4的致痉挛活性。在豚鼠中口服，该化合物阻断ltd4诱导的支气管收缩（ED50 = 0.8 mg/kg）和抗原诱导的全身过敏反应（ED50 = 1.2 mg/kg）。
This paper is the third in a series outlining the development of orally active sulfido peptide leukotriene antagonists containing a (quinolin-2-ylmethoxy)phenyl moiety. In this work the systematic variation of the acid side chain substituents led to dramatic and reproducible changes in the oral activity of these compounds, presumably due to alterations in their pharmacokinetic properties. The most potent compound identified, 5-[4-[4-(quinolin-2-yl-methoxy)phenyl]-3-methylbutyl]tetrazole (32), represents a convergence of good in vitro antagonist activity and a 3-10-fold improvement in oral potency over the current clinical candidate 2. The new findings from these optimization studies are as follows: oxygen substitution in the acid side chain was not necessary for antagonist activity, in vitro and in vivo activity was enhanced by alkyl or phenyl substitution on the .gamma.-carbon of the acid side chain of para-substituted (quinolin-2-ylmethoxy)phenyl derivatives, and free rotation about the side chain carbon atom adjacent to the (quinolin-2-ylmethoxy)phenyl ring was required for activity. The lead compound of this report (32) is a competitive inhibitor of [3H]LTD4 binding to receptor membrane purified from guinea pig lung (Ki = 12 .+-. 3 nM) and of the spasmogenic activity of LTC4, LTD4, and LTE4 in guinea pig lung strip. Dosed orally in guinea pigs, this compound blocks LTD4-induced bronchoconstriction (ED50 0.8 mg/kg) and antigen-induced systemic anaphylaxis (ED50 = 1.2 mg/kg).