Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P1) Employing Ligand-Based Drug Design.

Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.

Isolation of methyl 27-caffeoyloxyoleanolate--a new oleanane Triterpenoid from the roots of Hibiscus vitifolius.

A new oleanane triterpenoid, methyl 27-caffeoyloxyoleanolate (2), together with eight known compounds viz. oleanolic acid, kaempferol, quercetin, beta-sitosterol-3-O-beta-D-glucopyranoside, kaempferol-3-O-alpha-D-rhamnopyranoside, gossypin, quercetin-3-O-beta-D-glucopyranoside and mangiferin were isolated from the ethanol extract of roots of Hibiscus vitifolius Linn. The structure of the new compound 2 was elucidated from spectroscopic, ESI-MS and physical data. The eight known compounds were identified by comparison of their physical and spectroscopic data with those reported in the literature.