1,3,6-三取代-4-氧代-1,4-二氢喹啉-2-羧酸类化合物的合成及作为选择性内皮素 A 受体拮抗剂的活性。

Synthesis and pharmacological activity of 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acids as selective ET(A) antagonists.

机构信息

Department of Pharmaceutical Sciences, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA.

出版信息

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6840-4. doi: 10.1016/j.bmcl.2010.08.074.

DOI:10.1016/j.bmcl.2010.08.074

PMID:20932745

Abstract

A series of 1,3,6-trisubsituted-4-oxo-1,4-dihyroquinoline-2-carboxylic acid analogs (2a-m) were designed and synthesized and their pharmacological activity determined, with the objective to better understand their SAR as potential ET(A) selective inhibitors. Most of the compounds displayed significant ET(A) antagonist activity having IC(50) for inhibition of binding of the [(125)I]ET-1 to ET(A) receptor <10 nM, with good selectivity for ET(A) antagonism over ET(B) receptor. Based on the in vitro results, SAR of this series of compounds requires an alkoxy substituent at the 6-position to be a straight and saturated chain up to three carbons long, since substitution of unsaturated and branched alkyloxy groups results in decrease in ET(A) antagonist activity. In this series, compound 2c (6-O-n-propyl analog) was found to be most potent (IC(50)=0.11 nM) with ET(B)/ET(A) selectivity of 8303.

摘要

设计并合成了一系列 1,3,6-三取代-4-氧代-1,4-二氢喹啉-2-羧酸类似物（2a-m），并测定了它们的药理活性，旨在更好地了解它们作为潜在 ET(A)选择性抑制剂的 SAR。大多数化合物表现出显著的 ET(A)拮抗剂活性，对 [(125)I]ET-1 与 ET(A)受体结合的抑制作用的 IC(50) <10 nM，对 ET(A)拮抗作用具有良好的选择性，超过 ET(B)受体。基于体外结果，该系列化合物的 SAR 需要在 6 位具有烷氧基取代基，并且链长为直链且饱和，最长可达三个碳原子，因为不饱和和支链烷氧基取代基的取代会导致 ET(A)拮抗剂活性降低。在该系列中，发现化合物 2c（6-O-正丙基类似物）的活性最强（IC(50)=0.11 nM），对 ET(B)/ET(A)的选择性为 8303。