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
N-substituted azaindoles were discovered as potent pan-PIM inhibitors. Lead optimization, guided by structure and focused on physico-chemical properties allowed us to solve inherent hERG and permeability liabilities, and provided compound 27, which subsequently impacted KG-1 tumor growth in a mouse model.
Subject(s)
Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Aza Compounds/chemical synthesis , Aza Compounds/metabolism , Cell Line, Tumor , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/metabolism , Mice , Piperidines/chemical synthesis , Piperidines/metabolism , Piperidines/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Rats , Stereoisomerism , Xenograft Model Antitumor AssaysABSTRACT
N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 showed tumor growth inhibition in a KG1 tumor-bearing mouse model.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indoles/administration & dosage , Indoles/chemistry , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-pim-1/metabolism , Rats , Structure-Activity RelationshipABSTRACT
N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/metabolism , Animals , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Half-Life , Humans , Indoles/metabolism , Inhibitory Concentration 50 , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-pim-1/chemistry , Rats , Structure-Activity RelationshipABSTRACT
A solid phase combinatorial library was designed based on X-ray structures and in-silico models to explore an inducible S4+ pocket, which is formed by a simple side-chain rotation of Tyr95. This inducible S4+ pocket is unique to ß-tryptase and does not exist for other trypsin-like serine proteases of interest. Therefore, inhibitors utilizing this pocket have inherent advantages for being selective against other proteases in the same family. A member of this library was found to be a potent and selective ß-tryptase inhibitor with a suitable pharmacokinetic profile for further clinical evaluation.
Subject(s)
Enzyme Inhibitors/pharmacology , Mast Cells/enzymology , Small Molecule Libraries/pharmacology , Tryptases/antagonists & inhibitors , Administration, Oral , Animals , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Molecular Structure , Rats , Recombinant Proteins/antagonists & inhibitors , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemical synthesis , Structure-Activity RelationshipABSTRACT
A new series of novel mast cell tryptase inhibitors is reported, which features the use of an indole structure as the hydrophobic substituent on a m-benzylaminepiperidine template. The best members of this series display good in vitro activity and excellent selectivity against other serine proteases.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Mast Cells/enzymology , Serine Endopeptidases/drug effects , Enzyme Inhibitors/chemistry , Models, Molecular , Structure-Activity Relationship , TryptasesABSTRACT
Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.
Subject(s)
Amides , Piperidines , Serine Endopeptidases/drug effects , Administration, Oral , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Biological Availability , Caco-2 Cells , Crystallography, X-Ray , Drug Design , Factor Xa Inhibitors , Humans , Liver/enzymology , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Protein Conformation , Rats , Recombinant Proteins/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , TryptasesABSTRACT
We exploit the concept of using hydrogen bonds to link multiple ligands for maintaining simultaneous interactions with polyvalent binding sites. This approach is demonstrated by the syntheses and evaluation of pseudo-bivalent ligands as potent inhibitors of human beta-tryptase.