ABSTRACT
A vinyl azide cyclization method was used to synthesize three different carbocyclic[g]indole scaffolds as inhibitors of human nonpancreatic secretory phospholipase A2. Each scaffold demonstrated potent enzyme activity in a chromogenic assay system, with select examples also demonstrating potent activity in a secondary DOC/PC assay. Compound 11, representative of the cyclopent[g]indole series, gave an IC50 of 10 nM for the inhibition of hnps-PLA2 in the chromogenic assay.
Subject(s)
Acetates/chemical synthesis , Cyclopentanes/chemical synthesis , Indoles/chemical synthesis , Phospholipases A/antagonists & inhibitors , Acetates/chemistry , Cyclopentanes/chemistry , Humans , Indoles/chemistry , Phospholipases A/chemistry , Phospholipases A2 , Structure-Activity RelationshipABSTRACT
We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole series, phenyl substituents tended to show greater selectivity against p38 MAPK than those comprised of the quinoline-4-yl moiety. We have also achieved co-crystallization and X-ray analysis of compounds 3 and 15, two potent examples of this new series, with the TbetaR-I receptor kinase domain.
Subject(s)
Activin Receptors, Type I/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Activin Receptors, Type I/metabolism , Adenosine Triphosphate/metabolism , Animals , Cells, Cultured , Crystallography, X-Ray , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Protein Serine-Threonine Kinases , Pyrazoles/metabolism , Pyrazoles/pharmacology , Quinolines/chemistry , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.
Subject(s)
Benzene Derivatives/chemical synthesis , Benzene Derivatives/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , 3T3 Cells , Adenosine Triphosphate/metabolism , Animals , Benzene Derivatives/chemistry , Benzene Derivatives/metabolism , Binding Sites , Cell Line , Crystallography, X-Ray , Enzyme Inhibitors/metabolism , Humans , Inhibitory Concentration 50 , Mice , Mink , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Models, Molecular , Protein Serine-Threonine Kinases/chemistry , Protein Structure, Tertiary , Pyrazoles/chemistry , Pyrazoles/metabolism , Receptors, Transforming Growth Factor beta/chemistry , Receptors, Transforming Growth Factor beta/metabolism , Spodoptera , Structure-Activity Relationship , p38 Mitogen-Activated Protein KinasesABSTRACT
2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) potentiators are ligands that act as positive allosteric modulators at the AMPA receptors. We recently disclosed a novel series of 2-arylpropylsulfonamides that were potent potentiators of responses mediated through AMPA receptors. To further define the structural requirements for activity in this series, new ring-constrained analogues were prepared and a new stereocenter was introduced. The potentiating activity was highly dependent on the stereochemistry at the 2-position of the disubstituted cyclopentane and was independent of the relative stereochemistry at the 1-position. Compound (R,R)-10 represents a potent, novel potentiator of iGluR4 flip receptors (EC(50) = 22.6 nM).
