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Aryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P1) Modulators: Optimization of the PK, PD, and Safety Profiles.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-08-11 , DOI: 10.1021/acsmedchemlett.0c00333 Zili Xiao 1 , Michael G Yang 1 , T G Murali Dhar 1 , Hai-Yun Xiao 1 , John L Gilmore 1 , David Marcoux 1 , Kim W McIntyre 1 , Tracy L Taylor 1 , Hong Shi 1 , Paul C Levesque 1 , Anthony M Marino 1 , Georgia Cornelius 1 , Arvind Mathur 1 , Ding Ren Shen 1 , Mary Ellen Cvijic 1 , Lois D Lehman-McKeeman 1 , Huadong Sun 1 , Jenny H Xie 1 , Percy H Carter 1 , Alaric J Dyckman 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-08-11 , DOI: 10.1021/acsmedchemlett.0c00333 Zili Xiao 1 , Michael G Yang 1 , T G Murali Dhar 1 , Hai-Yun Xiao 1 , John L Gilmore 1 , David Marcoux 1 , Kim W McIntyre 1 , Tracy L Taylor 1 , Hong Shi 1 , Paul C Levesque 1 , Anthony M Marino 1 , Georgia Cornelius 1 , Arvind Mathur 1 , Ding Ren Shen 1 , Mary Ellen Cvijic 1 , Lois D Lehman-McKeeman 1 , Huadong Sun 1 , Jenny H Xie 1 , Percy H Carter 1 , Alaric J Dyckman 1
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Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P1 differentiated modulators 3–6. The effects of analogs 3–6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d, and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2, compound 3d had a better profile in both potency (ED50 < 0.05 mg/kg) and predicted human half-life (t1/2 ∼ 5 days).
中文翻译：
芳基醚衍生的 Sphingosine-1-Phosphate 受体 (S1P1) 调节剂：PK、PD 和安全特性的优化。
旨在提高体内效力和减少1和2的消除半衰期的努力导致鉴定了芳醚和硫醚衍生的双环 S1P 1分化调节剂3 – 6。描述了类似物3 – 6对大鼠淋巴细胞减少的影响（所需药理学）以及肺和心血管相关影响（不良药理学）。优化芳醚系列的整体特性产生了3d，并且针对3d的心血管影响的预测安全边际对于人体研究来说足够大。重要的是，相比如图1和2所示，化合物3d在效力(ED 50 < 0.05 mg/kg)和预测的人类半衰期( t 1/2 ∼ 5天)方面具有更好的分布。
更新日期：2020-09-10
中文翻译：
芳基醚衍生的 Sphingosine-1-Phosphate 受体 (S1P1) 调节剂：PK、PD 和安全特性的优化。
旨在提高体内效力和减少1和2的消除半衰期的努力导致鉴定了芳醚和硫醚衍生的双环 S1P 1分化调节剂3 – 6。描述了类似物3 – 6对大鼠淋巴细胞减少的影响（所需药理学）以及肺和心血管相关影响（不良药理学）。优化芳醚系列的整体特性产生了3d，并且针对3d的心血管影响的预测安全边际对于人体研究来说足够大。重要的是，相比如图1和2所示，化合物3d在效力(ED 50 < 0.05 mg/kg)和预测的人类半衰期( t 1/2 ∼ 5天)方面具有更好的分布。
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