Identification and synthesis of potent and selective pyridyl-isoxazole based agonists of sphingosine-1-phosphate 1 (S1P1)

[Display omitted] The synthesis and structure–activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent ma...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2016-05, Vol.26 (10), p.2470-2474
Hauptverfasser:	Guo, Junqing, Watterson, Scott H., Spergel, Steven H., Kempson, James, Langevine, Charles M., Shen, Ding Ren, Yarde, Melissa, Cvijic, Mary Ellen, Banas, Dana, Liu, Richard, Suchard, Suzanne J., Gillooly, Kathleen, Taylor, Tracy, Rex-Rabe, Sandra, Shuster, David J., McIntyre, Kim W., Cornelius, Georgia, D’Arienzo, Celia, Marino, Anthony, Balimane, Praveen, Salter-Cid, Luisa, McKinnon, Murray, Barrish, Joel C., Carter, Percy H., Pitts, William J., Xie, Jenny, Dyckman, Alaric J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Arthritis, Experimental - drug therapy Chemistry Techniques, Synthetic Dose-Response Relationship, Drug Drug Evaluation, Preclinical - methods Fingolimod FTY720 Humans Isoxazole Isoxazoles - chemistry Isoxazoles - pharmacology Lymphocyte Count Lysophospholipids - agonists Male Rats, Inbred Lew Receptors, Lysosphingolipid - agonists S1P1 Sphingosine - agonists Sphingosine - analogs & derivatives Sphingosine-1-phosphate Sphingosine-1-phosphate 1 Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] The synthesis and structure–activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2016.03.105