去甲肾上腺素转运体强效选择性抑制剂WAY-260022的发现

Discovery of WAY-260022, a Potent and Selective Inhibitor of the Norepinephrine Transporter.

作者信息

Gavrin Lori K, Mahaney Paige E, Jenkins Douglas, Nogle Lisa M, Mugford Cheryl A, Huselton Christine, Leiter Jennifer, Johnston Grace H, Bray Jenifer A, Burroughs Kevin D, Cosmi Scott A, Alfinito Peter, Ho Douglas M, Deecher Darlene C, Trybulski Eugene J

机构信息

Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140.

Worldwide Medicinal Chemistry.

出版信息

ACS Med Chem Lett. 2010 Mar 25;1(3):91-5. doi: 10.1021/ml100009p. eCollection 2010 Jun 10.

DOI:10.1021/ml100009p

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4007968/

Abstract

The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction.

摘要

描述了一系列1-{(1S)-2-[氨基]-1-[3-(三氟甲氧基)苯基]乙基}环己醇类似物的效价和选择性。制备这些化合物是为了提高体外代谢稳定性并实现脑内渗透。发现化合物13（WAY-260022，NRI-022）是去甲肾上腺素再摄取的强效抑制剂，并且对5-羟色胺和多巴胺转运体表现出优异的选择性。此外，13在体温调节功能障碍的大鼠模型中表现出口服疗效。

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