Orally Active 7-Substituted (4-Benzyl-phthalazin-1-yl)-2-methyl-piperazin-1-yl]-nicotinonitriles as Active-site Inhibitors of Sphingosine-1-Phosphate Lyase for the Treatment of Multiple Sclerosis

Sphingosine-1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active-site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzyl-phthalazin-1-yl)-2-methyl-piperazin-1-yl]-nicotinonitrile 1 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the co-crystal structure of derivative 15 with the homodimeric human S1P lyase. 15 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis . In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases

Chiral N-salicylidene vanadyl carboxylate-catalyzed enantioselective aerobic oxidation of α-hydroxy esters and amides

A series of chiral vanadyl carboxylates derived from N-salicylidene-l-α-amino acids and vanadyl sulfate has been developed. These configurationally well defined complexes were examined for the kinetic resolution of double- and mono-activated 2° alcohols. The best chiral templates involve the combination of l-tert-leucine and 3,5-di-t-butyl-, 3,5-diphenyl-, or 3,4-dibromo-salicylaldehyde. The resulting vanadyl(V)-methoxide complexes after recrystallization from air-saturated methanol serve as highly enantioselective catalysts for asymmetric aerobic oxidation of α-hydroxyl-esters and amides with a diverse array of α-, O-, and N-substituents at ambient temperature in toluene. The asymmetric inductions of the oxidation process are in the range of 10 to >100 in terms of selectivity factors (k(rel)) in most instances. The previously undescribed aerobic oxidation protocol is also applicable to the kinetic resolution of C-13 taxol side chain with high selectivity factor (k(rel) = 35). X-ray crystallographic analysis of an adduct between a given vanadyl complex and N-benzyl-mandelamide allows for probing the stereochemical origin of the nearly exclusive asymmetric control in the oxidation process