Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes.
ABSTRACT 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.
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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. · 9.49 Impact Factor
Article: The new era of 1,2,4-oxadiazoles.[Show abstract] [Hide abstract]
ABSTRACT: The synthesis, the chemical and photochemical reactivity, and the use of 1,2,4-oxadiazoles in materials and as bioactive compounds have been reviewed. The material in this survey includes some historical background, general features, state-of-the-art applications together with a critical discussion about current limitations and suggestions for future developments.Organic & Biomolecular Chemistry 11/2009; 7(21):4337-48. · 3.57 Impact Factor
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ABSTRACT: A copper‐catalyzed reaction of propargyl 4,6‐di‐O‐acetyl‐2,3‐dideoxy‐α‐D‐erythro‐hex‐2‐enopyranoside with 3‐(4‐azidophenyl)‐1,2,4‐oxadiazoles gave the corresponding hexenopyranosides bearing an 1,2,4‐oxadiazole subunit in the aglyconic part of the molecule. The same reaction between ethyl 4‐azido‐2,3,4‐trideoxy‐α‐D‐erythro‐hex‐2‐enopyranoside and acetylenic 1,2,4‐oxadiazoles afforded the corresponding hexenopyranosides carrying a triazole and a 1,2,4‐oxadiazole ring at C‐4 of the carbohydrate. Combination of the two sequences gave hexenopyranosides displaying two 1,2,4‐oxadiazole subunits, each one being embedded in the C‐1 and C‐4 frameworks, of the carbohydrate moiety. A simple dihydroxylation reaction of these unsaturated carbohydrates yielded a series of mannopyranosides bearing one or two 1,2,4‐oxadiazole subunits at C‐1 or C‐4. These new compounds were evaluated for their cytotoxic activities against two cell strains: NCI‐H292 (lung carcinoma) and Hep‐2 (larynx carcinoma), some of them presenting impressive cell growth inhibitions.Journal of Carbohydrate Chemistry - J CARBOHYD CHEM. 01/2008; 27(4):258-277.