Discovery of Potent 3,5-Diphenyl-1,2,4-oxadiazole Sphingosine-1-phosphate-1 (S1P1) Receptor Agonists with Exceptional Selectivity against S1P2 and S1P3
- Zhen Li
- ,
- Weirong Chen
- ,
- Jeffrey J. Hale
- ,
- Christopher L. Lynch
- ,
- Sander G. Mills
- ,
- Richard Hajdu
- ,
- Carol Ann Keohane
- ,
- Mark J. Rosenbach
- ,
- James A. Milligan
- ,
- Gan-Ju Shei
- ,
- Gary Chrebet
- ,
- Stephen A. Parent
- ,
- James Bergstrom
- ,
- Deborah Card
- ,
- Michael Forrest
- ,
- Elizabeth J. Quackenbush
- ,
- L. Alexandra Wickham
- ,
- Hugo Vargas
- ,
- Rose M. Evans
- ,
- Hugh Rosen
- , and
- Suzanne Mandala
Abstract

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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