ABSTRACT
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). This resulted in the identification of a thienopyridine scaffold as a starting point to initiate medicinal chemistry. Further optimization of hit compound 1 resulted in the identification of brain penetrable, orally bioavailable compound 19, which showed efficacy in the in vivo pharmacodynamic models, indicating the potential to treat MLD with UGT8 inhibitors.
ABSTRACT
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. We checked if the pattern deciphered could lead to a putative reactive moiety. Finally we used the docking pose of 1 into this model of the modified CYP3A4 crystal structure to guide transformation of 1 into MBI-free H-PGDS inhibitors.
Subject(s)
Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A/metabolism , Indoles/pharmacology , Sulfonamides/pharmacology , Cytochrome P-450 CYP3A Inhibitors/chemical synthesis , Cytochrome P-450 CYP3A Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/metabolism , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistrySubject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/metabolism , Lipocalins/antagonists & inhibitors , Lipocalins/metabolism , Alzheimer Disease/drug therapy , Animals , Asthma/drug therapy , Dermatitis, Atopic/drug therapy , Drug Design , Humans , Intramolecular Oxidoreductases/chemistry , Leukodystrophy, Globoid Cell/drug therapy , Lipocalins/chemistry , Muscular Dystrophies/drug therapy , Niacinamide/analogs & derivatives , Niacinamide/chemistry , Piperidines/chemistry , Pulmonary Disease, Chronic Obstructive/drug therapy , Pyrazoles/chemistry , Pyrimidines/chemistry , Rhinitis, Allergic, Perennial/drug therapy , Spinal Cord Injuries/drug therapy , Thiazoles/chemistryABSTRACT
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.
Subject(s)
Adjuvants, Immunologic/chemistry , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/immunology , Animals , Binding Sites , Cell Division/drug effects , Drug Design , Edema/drug therapy , Enzyme Inhibitors/chemistry , Indoles/chemistry , Inhibitory Concentration 50 , Interleukin-2/pharmacology , Janus Kinase 3 , Mice , Oxyquinoline/chemistry , Phosphorylation/drug effects , Protein Binding , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
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).
