ABSTRACT
In this study, we describe the synthesis and structure-activity relationship (SAR) of a series of isoquinoline chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50=19 nM) in addition to the excellent functional antagonist activity (IC50=13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50=23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1 µM) or the enzymes COX-1 and COX-2 (IC50 >10 µM).
Subject(s)
Drug Design , Isoquinolines/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Th2 CellsABSTRACT
7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-ß (TGF-ß) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-ß-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals).
Subject(s)
Alopecia/drug therapy , Benzothiazoles/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Animals , Benzothiazoles/chemistry , Female , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Mice, Inbred C57BL , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism , Smad2 Protein/antagonists & inhibitors , Smad2 Protein/metabolism , Smad3 Protein/antagonists & inhibitors , Smad3 Protein/metabolism , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolismABSTRACT
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).
Subject(s)
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/chemistryABSTRACT
Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 µM) and COX-1 and COX-2 enzymes (IC(50)>10 µM).
Subject(s)
Isoquinolines/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Chemotaxis , Inhibitory Concentration 50 , Isoquinolines/chemistry , Models, Molecular , Prostaglandin-Endoperoxide Synthases/chemistry , Protein Binding , Protein Interaction Domains and Motifs , Receptors, Prostaglandin/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of 4-thiazolylimidazoles was synthesized as transforming growth factor-ß (TGF-ß) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-ß-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. N-{[5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-2-yl]methyl}butanamide 20, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC(50)=8.2nM) as well as inhibitory activity against TGF-ß-induced Smad2/3 phosphorylation at a cellular level (IC(50)=32nM).
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Drug Design , Humans , Imidazoles/chemical synthesis , Models, Molecular , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
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).
