ABSTRACT
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Subject(s)
Cicatrix/prevention & control , Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Skin/drug effects , Animals , Models, Molecular , Phosphorylation , Rats , Receptor, Transforming Growth Factor-beta Type IABSTRACT
The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.
Subject(s)
Benzofurans/chemical synthesis , Benzofurans/therapeutic use , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Neurodegenerative Diseases/drug therapy , Sulfonamides/chemical synthesis , Sulfonamides/therapeutic use , Transaminases/antagonists & inhibitors , Animals , Benzofurans/chemistry , Calcium/antagonists & inhibitors , Calcium/metabolism , Cells, Cultured , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Glutamic Acid/drug effects , Glutamic Acid/metabolism , Humans , In Vitro Techniques , Models, Molecular , Molecular Structure , Neurons/cytology , Neurons/drug effects , Rats , Rats, Inbred Lew , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.
Subject(s)
Caspase Inhibitors , Drug Design , Serpins/chemical synthesis , Serpins/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Viral Proteins , Binding Sites , Caspase 1/metabolism , Crystallography, X-Ray , Humans , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel class of reversible inhibitors of Interleukin-1beta-converting enzyme (ICE, caspase-1) were discovered by iterative structure-based design. Guided by the X-ray crystal structure of analogues 1, 7 and 10 bound to ICE, we have designed a nonpeptide series of small molecule inhibitors. These compounds incorporate an arylsulfonamide moiety which replaces Val-His unit (P3-P2 residues) amino acids of the native substrate. The synthesis of the core structure, structure-activity relationships (SARs), and proposed binding orientation based on molecular modeling studies for this series of ICE inhibitors are described.