New P2X3 receptor antagonists. Part 1: Discovery and optimization of tricyclic compounds

被引：4

作者：

Szanto, Gabor ^{[1
]}

Mako, Attila ^{[1
]}

Bata, Imre ^{[1
]}

Farkas, Bence ^{[1
]}

Kolok, Sandor ^{[1
]}

Vastag, Monika ^{[1
]}

Cselenyak, Attila ^{[1
]}

机构：

[1] Gedeon Richter Plc, 10,POB 27, H-1475 Budapest, Hungary

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 16期

关键词：

Purinergic receptor; ATP; Ion channel; P2X3; antagonist; HTS campaign; Airway hyperractivity; New binding site; Chirality; CACO-2;

D O I：

10.1016/j.bmcl.2016.07.009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Purinergic P2X3 receptors are trimeric ligand-gated ion channels whose antagonism is an appealing yet challenging and not fully validated drug development idea. With the aim of identification of an orally active, potent human P2X3 receptor antagonist compound that can penetrate the central nervous system, the compound collection of Gedeon Richter was screened. A hit series of tricyclic compounds was subjected to a rapid, two-step optimization process focusing on increasing potency, improving metabolic stability and CNS penetrability. Attempts resulted in compound 65, a potential tool compound for testing P2X3 inhibitory effects in vivo. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：3896 / 3904

页数：9

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