芳基醚衍生的1-磷酸鞘氨醇受体（S1P）调节剂：药代动力学、药效学和安全性的优化
Aryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P) Modulators: Optimization of the PK, PD, and Safety Profiles.
作者信息
Xiao Zili, Yang Michael G, Dhar T G Murali, Xiao Hai-Yun, Gilmore John L, Marcoux David, McIntyre Kim W, Taylor Tracy L, Shi Hong, Levesque Paul C, Marino Anthony M, Cornelius Georgia, Mathur Arvind, Shen Ding Ren, Cvijic Mary Ellen, Lehman-McKeeman Lois D, Sun Huadong, Xie Jenny H, Carter Percy H, Dyckman Alaric J
机构信息
Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
出版信息
ACS Med Chem Lett. 2020 Aug 11;11(9):1766-1772. doi: 10.1021/acsmedchemlett.0c00333. eCollection 2020 Sep 10.
Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of and led to the identification of aryl ether and thioether-derived bicyclic S1P differentiated modulators -. The effects of analogs - 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 , and the predicted margin of safety against the cardiovascular effects of would be large enough for human studies. Importantly, compared to and , compound had a better profile in both potency (ED < 0.05 mg/kg) and predicted human half-life ( ∼ 5 days).
旨在提高体内效力并缩短[具体药物1]和[具体药物2]消除半衰期的研究工作，促成了芳基醚和硫醚衍生的双环S1P差异化调节剂[具体化合物1]-[具体化合物2]的发现。描述了类似物[具体化合物1]-[具体化合物2]对大鼠淋巴细胞减少（预期药理学作用）以及与肺和心血管相关的作用（非预期药理学作用）。芳基醚系列整体性质的优化产生了[具体化合物3]，并且针对[具体化合物3]心血管作用的预测安全边际对于人体研究而言足够大。重要的是，与[具体化合物1]和[具体化合物2]相比，化合物[具体化合物3]在效力（ED<0.05mg/kg）和预测的人体半衰期（约5天）方面均具有更好的特性。
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