Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P(1)) with high selectivity against all other known S1P receptor subtypes
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 08/2006; 16(14):3679-83. DOI: 10.1016/j.bmcl.2006.04.084
A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2-5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.
- Annual reports in medicinal chemistry 01/2007; 42:245-263. DOI:10.1016/S0065-7743(07)42016-4 · 1.36 Impact Factor
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ABSTRACT: Structure-activity relationship (SAR) studies of 3-arylpropionic acids-a class of novel S1P(1) selective agonists-by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs (e.g., cyclopropanecarboxylic acids) exhibited longer half-life in rat than did unmodified 3-arylpropionic acids. This result suggests that metabolic oxidation at the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.Bioorganic & Medicinal Chemistry Letters 03/2007; 17(3):828-31. DOI:10.1016/j.bmcl.2006.10.057 · 2.42 Impact Factor
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ABSTRACT: The lysophospholipid sphingosine 1-phosphate (S1P) is a pleiotropic signaling lipid present constitutively in plasma, and secreted locally at elevated concentrations at sites of inflammation. S1P maintains essential variable homeostatic functions in addition to inducing pathophysiology through the activation of five specific high-affinity G-protein-coupled receptors. Therefore, S1P can function as an extracellular rheostat regulating tonic and acutely evoked functions. Although S1P receptors can regulate lymphoid development and lymphocyte trafficking, and different opinions exist on the roles of receptor agonism and functional antagonism in regulating lymphocyte recirculation, this personal perspective highlights the pivotal control points regulated by constitutive and induced S1P receptor tone at vascular endothelial and lymphatic endothelial barriers, through which S1P agonism impacts on both innate and adaptive immunity. We also emphasize how specific, proof-of-concept chemical tools complement genetic approaches by enabling reversible perturbation of the S1P-S1P(1) receptor axis and, thus, clarifying in vivo mechanisms in the absence of developmental compensations.Trends in Immunology 04/2007; 28(3):102-7. DOI:10.1016/j.it.2007.01.007 · 10.40 Impact Factor
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