1236188-83-2Relevant academic research and scientific papers
Potent and Selective Agonists of Sphingosine 1-Phosphate 1 (S1P1): Discovery and SAR of a Novel Isoxazole Based Series
Watterson, Scott H.,Guo, Junqing,Spergel, Steve H.,Langevine, Charles M.,Moquin, Robert V.,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,Warrack, Bethanne,Salter-Cid, Luisa,McKinnon, Murray,Barrish, Joel C.,Carter, Percy H.,Pitts, William J.,Xie, Jenny,Dyckman, Alaric J.
, p. 2820 - 2840 (2016/04/10)
Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.
Discovery and Structure-Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P1)
Gilmore, John L.,Sheppeck, James E.,Watterson, Scott H.,Haque, Lauren,Mukhopadhyay, Parag,Tebben, Andrew J.,Galella, Michael A.,Shen, Ding Ren,Yarde, Melissa,Cvijic, Mary Ellen,Borowski, Virna,Gillooly, Kathleen,Taylor, Tracy,McIntyre, Kim W.,Warrack, Bethanne,Levesque, Paul C.,Li, Julia P.,Cornelius, Georgia,D'Arienzo, Celia,Marino, Anthony,Balimane, Praveen,Salter-Cid, Luisa,Barrish, Joel C.,Pitts, William J.,Carter, Percy H.,Xie, Jenny,Dyckman, Alaric J.
, p. 6248 - 6264 (2016/07/26)
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).
HETEROCYCLIC COMPOUNDS AS S1P1 AGONISTS FOR THE TREATMENT OF AUTOIMMUNE AND VASCULAR DISEASES
-
, (2012/05/20)
Disclosed are compounds of Formula (I) or stereoisomers, salts, or prodrugs thereof, wherein: W is CH2 or O; Q is Formula (II), Formula (III) or Formula (IV); and R1, R2, R3, R4, n, and G are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
TRICYCLIC HETEROCYCLIC COMPOUNDS
-
Page/Page column 82-83, (2011/06/16)
Disclosed are compounds of Formula (I) or stereoisomers or salts thereof, wherein: X1, X2, X3, W, Q1, Q2, and G2 are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONISTS
-
, (2011/02/24)
Disclosed are compounds of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: A is formula (II) Q is a substituted 5-membered monocyclic heteroaryl group; W is CH2, O, or NH; and R1, R2, R3, R4, R5, R6, m, n, t, and x are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
4 - (5 - ISOXAZOLYL OR 5 - PYRRAZOLYL -1,2,4- OXADIAZOL - 3 - YL) -MANDELIC ACID AMIDES AS SPHINGOSIN- 1 - PHOSPHATE 1 RRECEPTOR AGONISTS
-
, (2011/11/06)
Disclosed are compounds of Formula (I) or stereoisomers, salts, or prodrugs thereof, wherein: Q is, or R1 is phenyl substituted with zero to 3 substituents; and R1, R2, R3, R4, R5, and G are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
SUBSTITUTED OXADIAZOLE DERIVATIVES AS S1P AGONISTS IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISEASES
-
Page/Page column 56, (2010/08/08)
Disclosed are compounds of Formula (I) [INSERT CHEMICAL STRUCTURE HERE] (I) or pharmaceutically acceptable salts thereof, wherein Q is [INSERT CHEMICAL STRUCTURE HERE] or [INSERT CHEMICAL STRUCTURE HERE]; R1 is alkyl or aryl, said aryl optionally substituted with one to five substituents independently selected from C1 to C6 alkyl, C1 to C4 haloalkyl, OR4, and/or halogen; and R2, R3, R4, and n are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
