Aryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P<sub>1</sub>) Modulators: Optimization of the PK, PD, and Safety Profiles.
Xiao Z, Yang MG, Dhar TGM, Xiao HY, Gilmore JL, Marcoux D, McIntyre KW, Taylor TL, Shi H, Levesque PC, Marino AM, Cornelius G, Mathur A, Shen DR, Cvijic ME, Lehman-McKeeman LD, Sun H, Xie JH, Carter PH, Dyckman AJ.
Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of <b>1</b> and <b>2</b> led to the identification of aryl ether and thioether-derived bicyclic S1P<sub>1</sub> differentiated modulators <b>3</b>-<b>6</b>. The effects of analogs <b>3</b>-<b>6</b> 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 <b>3d</b>, and the predicted margin of safety against the cardiovascular effects of <b>3d</b> would be large enough for human studies. Importantly, compared to <b>1</b> and <b>2</b>, compound <b>3d</b> had a better profile in both potency (ED<sub>50</sub> < 0.05 mg/kg) and predicted human half-life (<i>t</i> <sub>1/2</sub> ∼ 5 days).