Brain Penetrable Inhibitors of Ceramide Galactosyltransferase for the Treatment of Lysosomal Storage Disorders.

Metachromatic leukodystrophy (MLD) is a rare, genetic lysosomal storage disorder caused by the deficiency of arylsulfatase A enzyme, which results in the accumulation of sulfatide in the lysosomes of the tissues of central and peripheral nervous systems, leading to progressive demyelination and neurodegeneration. Currently there is no cure for this disease, and the only approved therapy, hematopoietic stem cell transplant, has limitations. We proposed substrate reduction therapy (SRT) as a novel approach to treat this disease, by inhibiting ceramide galactosyltransferase enzyme (UGT8).

Amelioration of mechanism-based inactivation of CYP3A4 by a H-PGDS inhibitor.

This work describes the rational amelioration of mechanism-based inactivation (MBI) of Cytochrome P450 (CYP) 3A4 in a human hematopoietic prostaglandin D synthase (hH-PGDS) inhibitor (cpd 1). We utilized metabolism reports in order to check if patterns in the metabolism of 1 and similar compounds by CYP3A4 could be deciphered. Then we used structure based design, first modifying the CYP3A4 crystal structure (pdb code: 4NY4) by adding an oxyferryl moiety to the heme, followed by validating the modified structure to obtain the 1' and 4 position oxidation products of midazolam and then recapitulating the metabolism patterns deciphered previously for 1 and analogs.

Potent small molecule inhibitors of spleen tyrosine kinase (Syk).

A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).

Mapping the kinase domain of Janus Kinase 3.

The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.