Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.
Enzyme Precursors , Matrix Metalloproteinase 9 , Matrix Metalloproteinase 9/metabolism , Enzyme Precursors/metabolism , Extracellular Matrix/metabolism , Indoles/pharmacology , Indoles/metabolism , Metalloendopeptidases/metabolism , Matrix Metalloproteinase Inhibitors
Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure-activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase γ (PI3Kγ). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration.
Arthritis, Experimental/drug therapy , Drug Discovery , Enzyme Inhibitors/pharmacology , Oxadiazoles/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Thiazoles/pharmacology , Administration, Oral , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/enzymology , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Collagen , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Male , Mice , Mice, Inbred DBA , Molecular Structure , Oxadiazoles/administration & dosage , Oxadiazoles/chemistry , Structure-Activity Relationship , Thiazoles/administration & dosage , Thiazoles/chemistry
A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-ß (TGF-ß) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-ß-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC(50) = 5.5 nM) as well as inhibitory activity against TGF-ß-induced Smad2/3 phosphorylation at a cellular level (IC(50) = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).
Imidazoles/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Animals , Female , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Serine-Threonine Kinases/chemistry , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/chemistry
A novel series of 2-aminothiazole-oxazoles was designed and synthesized as part of efforts to develop potent phosphoinositide 3-kinase γ (PI3Kγ) inhibitors. The modification of a high-throughput screening hit, compound 1, resulted in the identification of compounds 10 and 15, which displayed potent inhibitory activities in enzyme-based and cell-based assays.
Drug Discovery , Oxazoles/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Thiazoles/pharmacology , Animals , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Macrophages/drug effects , Macrophages/enzymology , Macrophages/metabolism , Mice , Models, Molecular , Molecular Structure , Oxazoles/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , Thiazoles/chemistry
We have identified a novel series of ring-fused pyrazole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <1nM) as well as excellent cellular activity against mixed lymphocyte reaction (MLR) (IC(50)s <1nM).
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrroles/chemistry , Adenosine Triphosphate/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Hydrogen Bonding , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Lymphocytes/drug effects , Lymphocytes/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Structure-Activity Relationship
We have described the synthesis, enzyme inhibitory activity, structure-activity relationships, and proposed binding mode of a novel series of pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <10nM) for Lck kinase inhibition.
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrroles/chemical synthesis , Adenosine Triphosphate/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Hydrogen Bonding , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Lymphocytes/drug effects , Lymphocytes/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship
Racemic 1- and 2-naphthylmethoxyacetic acids (1NMA and 2NMA), the chiral anisotropic reagents used for absolute configuration determination of chiral secondary alcohols and primary amines, were conveniently resolved to enantiomers (>99% ee) by condensation with L-phenylalaninol (2-amino-3-phenylpropanol), chromatographic separation of the diastereomers, and hydrolysis. This method enables large-scale preparation of enantiomeric 1NMA and 2NMA.
