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Discovery of Potent 3,5-Diphenyl-1,2,4-oxadiazole Sphingosine-1-phosphate-1 (S1P1) Receptor Agonists with Exceptional Selectivity against S1P2 and S1P3

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Departments of Medicinal Chemistry and Immunology & Rheumatology Research, Merck Research Laboratories, Rahway, New Jersey 07065, and Department of Preclinical Safety Evaluation, Merck Research Laboratories, West Point, Pennsylvania 19486
Cite this: J. Med. Chem. 2005, 48, 20, 6169–6173
Publication Date (Web):September 10, 2005
https://doi.org/10.1021/jm0503244
Copyright © 2005 American Chemical Society

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    Abstract

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    A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.

    *

     To whom correspondence should be addressed. Phone:  (732) 594-8319. Fax:  (732) 594-8080. E-mail:  [email protected].

     Department of Medicinal Chemistry.

     Current address:  Millennium Pharmaceuticals Inc., 35 Landsowne Street, Cambridge, MA 02139.

     Current address:  Abbott Laboratories, Building AP-10, 100 Abbott Park Road, Abbott Park, IL 60064.

    §

     Department of Immunology & Rheumatology.

    #

     Department of Preclinical Safety Evaluation.

     Current address:  The Scripps Research Institute, ICND-118, 10550 N. Torrey Pines Road, La Jolla, CA 92037.

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    Experimental details and characterization data for final in vivo tested compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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