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. 2020 Aug 11;11(9):1766-1772.
doi: 10.1021/acsmedchemlett.0c00333. eCollection 2020 Sep 10.

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

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
Affiliations

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

Zili Xiao et al. ACS Med Chem Lett. .

Abstract

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).

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
S1P1 compounds 3–6 with heteroatom-linked side chains.
Figure 2
Figure 2
Reduction in beating rate of human iPSCs-derived cardiomyocytes.
Figure 3
Figure 3
Lymphocyte reduction vs BAL protein exposure in Lewis rats comparing 3d and 4b (left panel); lymphocyte reduction vs BAL protein exposure of 3d in Lewis rats (right panel). *p < 0.05 vs Vehicle, ANOVA w/ Dunnett’s; Mean +/– SEM, n = 2–3/group.
Scheme 1
Scheme 1. Representative Examples for the Preparations of 3–6
Reagents and conditions: (a) Step-1, potassium tert-butoxide, t-BuOH, ArOH, 70 °C, 16 h; step-2: LiOH, dioxane/H2O, 90 °C; (b) Step-1, potassium tert-butoxide, t-BuOH, ArSH, 70 °C, 16 h; step-2: LiOH, dioxane/H2O, 90 °C; (c) Step-1, potassium tert-butoxide, t-BuOH, BnOH, 70 °C, 16 h; step-2: LiOH, dioxane/H2O, 90 °C; (d) NaBH4, MeOH, 0 °C; (e) Potassium tert-butoxide, 1-(bromomethyl)-3-methoxybenzene, −50 °C → rt over 16 h; (f) LiOH, dioxane/H2O, 100 °C; (g) Chiral SFC separation, 14–17% yield over four steps.
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