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

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

  • ACS Med Chem Lett. 2020 Aug 11;11(9):1766-1772. 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
Affiliations

Affiliation

  • 1 Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
PMID: 32944145 DOI: 10.1021/acsmedchemlett.0c00333
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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