ABSTRACT
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DKD pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DKD.
Subject(s)
Diabetic Nephropathies/enzymology , Fibroblasts/enzymology , Kidney Glomerulus/enzymology , MAP Kinase Kinase Kinase 5/metabolism , MAP Kinase Signaling System , Animals , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Disease Models, Animal , Female , Fibroblasts/pathology , Fibrosis , Humans , Kidney Glomerulus/pathology , MAP Kinase Kinase Kinase 5/antagonists & inhibitors , MAP Kinase Kinase Kinase 5/genetics , Male , Mice , Mice, Knockout , Protein Kinase Inhibitors/pharmacology , Random Allocation , Rats, Sprague-DawleyABSTRACT
We report the palladium-catalyzed enantioselective cyclization of 1,6-enamidynes to form spirocyclic ring systems. We applied this methodology to the concise synthesis of the skeletal core of the kopsifoline alkaloids.
ABSTRACT
The discovery of complementary methods for enantioselective transition metal-catalyzed cyclization with silyloxyenynes has been accomplished using chiral phosphine ligands. Under palladium catalysis, 1,6-silyloxyenynes bearing a terminal alkyne led to the desired five-membered ring with high enantioselectivities (up to 91% ee). As for reactions under cationic gold catalysis, 1,6- and 1,5-silyloxyenynes bearing an internal alkyne furnished the chiral cyclopentane derivatives with excellent enantiomeric excess (up to 94% ee). Modification of the substrate by incorporating an α,ß-unsaturation led to the discovery of a tandem cyclization. Remarkably, using silyloxy-1,3-dien-7-ynes under gold catalysis conditions provided the bicyclic derivatives with excellent diastereo- and enantioselectivities (up to >20:1 dr and 99% ee).
Subject(s)
Alkynes/chemistry , Gold/chemistry , Organosilicon Compounds/chemistry , Phosphines/chemistry , Cations/chemistry , Cyclization , Molecular Structure , StereoisomerismSubject(s)
Alkynes/chemistry , Silanes/chemistry , Catalysis , Cyclization , Palladium/chemistry , StereoisomerismSubject(s)
Ethers/chemistry , Gold/chemistry , Organosilicon Compounds/chemical synthesis , Sesquiterpenes/chemical synthesis , Alkadienes/chemistry , Alkynes/chemistry , Catalysis , Cyclization , Molecular Structure , Organosilicon Compounds/chemistry , Oxidation-Reduction , Sesquiterpenes/chemistry , StereoisomerismABSTRACT
An enantioselective intramolecular Conia-ene reaction of beta-dicarbonyl compounds and alkynes to afford methylene cyclopentanes is described. The reaction employs a DTBMSegphos-Pd(II)/Yb(III) dual catalyst system that allows for the asymmetric synthesis of all-carbon quaternary centers and generates a product containing an alkene that can be further manipulated.
