Aryl Ether-Derived Sphingosine-1-Phosphate Receptor
(S1P1) Modulators: Optimization of the PK, PD, and Safety
Profiles

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.

doi:10.1021/acsmedchemlett.0c00333.s001

Aryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P₁) Modulators: Optimization of the PK, PD, and Safety Profiles

journal contribution

posted on 2020-08-14, 17:35 authored by Zili Xiao, Michael G. Yang, T. G. Murali Dhar, Hai-Yun Xiao, John L. Gilmore, David Marcoux, Kim W. McIntyre, Tracy L. Taylor, Hong Shi, Paul C. Levesque, Anthony M. Marino, Georgia Cornelius, Arvind Mathur, Ding Ren Shen, Mary Ellen Cvijic, Lois D. Lehman-McKeeman, Huadong Sun, Jenny H. Xie, Percy H. Carter, Alaric J. Dyckman

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 (t_1/2 ∼ 5 days).