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

Szanto Gabor; Mako Attila; Bata Imre; Farkas Bence; Kolok Sandor; Vastag Monika; Cselenyak Attila

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

机译：新的P2X3受体拮抗剂。第1部分：三环化合物的发现和优化

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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.

机译：嘌呤能P2X3受体是三聚体配体门控离子通道，其拮抗作用是吸引人的但具有挑战性且尚未得到充分验证的药物开发构想。为了鉴定可以穿透中枢神经系统的口服活性，有效的人P2X3受体拮抗剂化合物，筛选了Gedeon Richter的化合物集合。对一系列命中的三环化合物进行了快速的两步优化过程，重点是提高效力，改善代谢稳定性和CNS渗透性。尝试产生了化合物65，这是一种在体内测试P2X3抑制作用的潜在工具化合物。（C）2016 Elsevier Ltd.保留所有权利。

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《Bioorganic and Medicinal Chemistry Letters》 |2016年第16期|共9页
作者
Szanto Gabor; Mako Attila; Bata Imre; Farkas Bence; Kolok Sandor; Vastag Monika; Cselenyak Attila;
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正文语种 eng
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关键词
Purinergic receptor; ATP; Ion channel; P2X3 antagonist; HTS campaign; Airway hyperractivity; New binding site; Chirality;

机译：嘌呤能受体;ATP;离子通道;P2X3拮抗剂;HTS运动;气道过度反应;新结合位点;周期性;

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1. New P2X3 receptor antagonists. Part 1: Discovery and optimization of tricyclic compounds [J] . Szanto Gabor, Mako Attila, Bata Imre, Bioorganic and Medicinal Chemistry Letters . 2016,第16期

机译：新的P2X3受体拮抗剂。第1部分：三环化合物的发现和优化
2. Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist. [J] . Brotherton Pleiss CE, Dillon MP, Ford A Bioorganic and Medicinal Chemistry Letters . 2010,第3期

机译：发现和优化RO-85，这是一种新型的药物样有效，选择性P2X3受体拮抗剂。
3. Discovery and structure-activity relationships of new steroidal compounds bearing a carboxy-terminal side chain as androgen receptor pure antagonists. [J] . Tachibana K, Imaoka I, Yoshino H, Bioorganic and Medicinal Chemistry Letters . 2007,第20期

机译：具有雄激素受体纯拮抗剂的带有羧基末端侧链的新型甾族化合物的发现与构效关系。
4. Discovery and Structural Optimization of High Affinity Co-Agonists at the Glucagon and GLP-1 Receptors [C] . Tao Ma, Jonathan Day, Vasily Gelfanov American Peptide Symposium . 2009

机译：胰高血糖素和GLP-1受体的高亲和力共激剂的发现与结构优化
5. Computer-aided discovery of novel natural product inhibitors of receptor tyrosine kinases and their rational semisynthetic optimizations for multiple malignancies control. [D] . Mohyeldin, Mohamed M. 2016

机译：计算机辅助发现的受体酪氨酸激酶的新型天然产物抑制剂及其对多种恶性肿瘤的合理的半合成优化。
6. Discovery and Optimization of Potent GPR40 Full AgonistsContaining Tricyclic Spirocycles [O] . Yingcai Wang, *, Jiwen (Jim) Liu, 2013

机译：高效GPR40全激动剂的发现和优化含三环螺环
7. Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. I. Design and Synthesis of (.+-.)-N-(2-(3,4-Dichlorophenyl)-4-(spiro(isobenzofuran-1(3H),4'-piperidin)-1'-yl)butyl)-N-methylbenzamide, YM-35375, as a New Lead Compound for Novel Neurokinin Receptor Antagonists. [O] . Hirokazu KUBOTA, Masahiro FUJII, Ken IKEDA, 1998

机译：螺替代的哌啶作为神经激素受体拮抗剂。 I.（。+ - 。） - N-（2-（3,4-二氯苯基）-4-（螺呋喃 - 1（3H），4'-哌啶）-1'-y1）丁基的设计和合成）-N-甲基苄酰胺，YM-35375，作为新型神经蛋白受体拮抗剂的新型铅化合物。
8. How Spare Receptors Oppose the Action of Certain Antagonists. [R] . Nielsen, T. B. 1987

机译：备用受体如何反对某些反对者的行为。

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

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