BACKGROUND AND PURPOSESphingosine1-phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P 1 receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non-selective S1P modulator, FTY720 (fingolimod, Gilenya ™ ). The purpose of this study was to assess RPC1063 for its therapeutic utility in autoimmune diseases. EXPERIMENTAL APPROACHThe specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P 1 receptor expression, was characterized in vitro. The oral pharmacokinetic (PK) parameters and pharmacodynamic effects were established in rodents, and its activity in three models of autoimmune disease (experimental autoimmune encephalitis, 2,4,6-trinitrobenzenesulfonic acid colitis and CD4 + CD45RB hi T cell adoptive transfer colitis) was assessed. KEY RESULTSRPC1063 was specific for S1P 1 and S1P 5 receptors, induced S1P 1 receptor internalization and induced a reversible reduction in circulating B and CCR7 + T lymphocytes in vivo. RPC1063 showed high oral bioavailability and volume of distribution, and a circulatory half-life that supports once daily dosing. Oral RPC1063 reduced inflammation and disease parameters in all three autoimmune disease models. CONCLUSIONS AND IMPLICATIONSS1P receptor selectivity, favourable PK properties and efficacy in three distinct disease models supports the clinical development of RPC1063 for the treatment of relapsing multiple sclerosis and inflammatory bowel disease, differentiates RPC1063 from other S1P receptor agonists, and could result in improved safety outcomes in the clinic.

The [2+2+2] cycloaddition strategy is complementary to the well known Diels-Alder reaction for the generation of polycyclic compounds. This [2+2+2] approach is atom-economical and, with the availability of new catalysts to effect the [2+2+2] cycloaddition reaction, synthesis of a wide variety of highly functionalized polycycles is possible. This review deals with some recent advances relating to [2+2+2] cycloaddition reactions involving the syntheses both of polycycles

Conformationally constrained cyclic alpha-amino acid derivatives were synthesized under solid-liquid phase-transfer catalysis conditions. This methodology involves the bis-alkylation of ethyl isocyanoacetate with various alpha,alpha'-dibromo-o-xylene derivatives [alpha,alpha'-dibromo-o-xylene 5, 2,3-bis(bromomethyl)-1, 4-dimethoxybenzene 6, 1,2-bis(bromomethyl)-4,5-dibromobenzene 7, 2, 3-bis(bromomethyl)naphthalene 8, 1,8-bis(bromomethyl)-naphthalene 9, 6,7-bis(bromomethyl)-2,2-dimethyl-1H-phenalene-1,3(2H)-dione 10, 2, 3-bis(bromomethyl)-1,4-anthraquinone 11, 6, 7-bis(bromomethyl)quinoxaline 12, 3,4-bis(bromomethyl)furan 13, 1,2, 4,5-tetrakis(bromomethyl)benzene 28, and hexakis(bromomethyl)benzene 30] using potassium carbonate as a base and tetrabutylammonium hydrogensulfate as a phase-transfer catalyst to give corresponding isonitrile derivatives, which upon hydrolysis with HCl in ethanol gave amino esters. Using this method electron-deficient as well as electron-rich and halogen-substituted indan-based alpha-amino acids were prepared. The preparation of bis-indan as well as tris-indan alpha-amino esters is also described.

One pot synthesis of 1, 3, 5-tris(thienyl)benzene derivatives via tetrachlorosilane mediated trimerization reaction is described. Substituted thiophenes are valuable building blocks in many natural and non-natural products and enjoy potential applications in flavor and pharmaceutical industries. 2 In addition to these synthetic implications, thiophenes occur abundantly as structural units in many natural molecules. 3 Raney nickel desulfurization has made thiophenes as useful intermediates for the preparation of the aliphatic compounds. 4 Moreover, a number of substituted thiophenes are apt to give sulfones, yielding non-aromatic compounds which undergo Diels-Alder reaction to generate the polycyclics. 5,6 Due to the intractable nature of polythiophene (PT) there is a need to modify PT to make it as processible as conventional organic polymers. 7 Oligothiophenes are useful model systems for PT and in this regard Garnier and coworkers 8 have shown that the semiconducting properties of PT are already present in α-conjugated sexithienyl. For design of the new generation of polymers more knowledge is required for the monomer preparation.In connection with our interest in unusual amino acids preparation via building block approach 9 we conceived the building blocks containing C 3 -symmetry element is an attractive option. 1 In this regard, we identified cyclotrimerization of carbonyl compounds as a useful strategy. 10 Some of these C 3 -symmetric building blocks are also useful in the preparation of dendrimer molecules 11 and fullerene fragments. 12 For example, oxidation of 1 followed by Diels-Alder reaction with the appropriately substituted acetylenic dienophiles is expected to give inaccessible 1, 3, 5-triphenyl benzene derivatives (e.g., 3, Scheme 1). 10 Compound 2 is a useful starting material for the synthesis of C 3 -symmetric amino acids by asymmetric derivatization of glycine moiety. Similarly, monoacetylation and trimerization of compound 1 may generate mixed aryl-thienyl oligomer. Our attempts to use repetitive acetylation and trimerization sequence starting from acetophenone to generate dendrimers via 3 was not realized due to the insoluble nature of polyphenyl hydrocarbons (PPHs). At this juncture we reasoned out that the heteroaromatic systems may obviate the problems associated with the PPHs. In this regard, we attempted tetrachlorosilane (SiCl 4 ) mediated trimerization of 2-acetylfuran and found that a complex mixture of products was formed. In view of the ring opening reactions of furan under acidic conditions, this result was not surprising to us. Scheme 1Since, thiophene derivatives are more stable to various Lewis acid conditions, we next tried the trimerization reaction of 2-acetylthiophene 4 which can be prepared by treatment of thiophene with acetic anhydride / phosphoric acid at 70-75 o C. 13 Treatment of 4 with SiCl 4 at room temperature gave 1 in 42% yield after chromatography. After completion of our work 1 preparation of compound 1 is reported by an indirect route involving Pd mediated ...

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