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5-苯基-N-(吡啶-2-基甲基)-2-(嘧啶-5-基)喹唑啉-4-胺作为一种强效I Kur抑制剂的发现。

Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent I Kur Inhibitor.

作者信息

Finlay Heather J, Johnson James A, Lloyd John L, Jiang Ji, Neels James, Gunaga Prashantha, Banerjee Abhisek, Dhondi Naveen, Chimalakonda Anjaneya, Mandlekar Sandhya, Conder Mary Lee, Sale Harinath, Xing Dezhi, Levesque Paul, Wexler Ruth R

机构信息

Departments of Discovery Chemistry, Biology, and Preclinical Candidate Optimization, Bristol-Myers Squibb, Research and Development , P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.

Departments of Discovery Chemistry, Biology, and Preclinical Candidate Optimization, Biocon Bristol-Myers Squibb Research Center (BBRC) , Bangalore 560099, India.

出版信息

ACS Med Chem Lett. 2016 Jun 9;7(9):831-4. doi: 10.1021/acsmedchemlett.6b00117. eCollection 2016 Sep 8.

DOI:10.1021/acsmedchemlett.6b00117
PMID:27660686
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5018869/
Abstract

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

摘要

公开了一系列新型Kv 1.5的苯基喹唑啉抑制剂。该系列针对Kv 1.5效力、对hERG的选择性、药代动力学暴露和药效学效力进行了优化。5-苯基-N-(吡啶-2-基甲基)-2-(嘧啶-5-基)喹唑啉-4-胺(13k)被鉴定为一种强效且离子通道选择性抑制剂，在临床前大鼠心室有效不应期(VERP)模型和兔心房有效不应期(AERP)模型中具有强大的疗效。

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