ABSTRACT
We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.
Subject(s)
ADAM17 Protein/antagonists & inhibitors , Hydantoins/chemistry , Protease Inhibitors/chemistry , ADAM17 Protein/metabolism , Animals , Area Under Curve , Dogs , Enzyme Activation/drug effects , Half-Life , Haplorhini , Humans , Hydantoins/chemical synthesis , Hydantoins/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , ROC Curve , Rats , Structure-Activity RelationshipABSTRACT
TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Amides/pharmacology , Enzyme Inhibitors/pharmacology , Pyrrolidines/chemistry , Tartrates/chemistry , ADAM17 Protein , Amides/chemical synthesis , Amides/chemistry , Animals , Biological Availability , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Molecular Structure , RatsABSTRACT
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Anti-Inflammatory Agents/chemistry , Arthritis, Rheumatoid/drug therapy , Protease Inhibitors/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Acetylene/analogs & derivatives , Acetylene/pharmacokinetics , Acetylene/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Dogs , Haplorhini , Humans , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/therapeutic use , RatsABSTRACT
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , ADAM17 Protein , Animals , Rats , Structure-Activity RelationshipABSTRACT
The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Protease Inhibitors/chemistry , Tartrates/chemistry , ADAM Proteins/metabolism , ADAM17 Protein , Animals , Binding Sites , Computer Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Tartrates/chemical synthesis , Tartrates/pharmacokineticsABSTRACT
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Hydantoins/pharmacology , ADAM17 Protein , Enzyme Inhibitors/chemistry , Hydantoins/chemistry , Hydrogen Bonding , Models, Molecular , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Subject(s)
ADAM Proteins/antagonists & inhibitors , ADAM Proteins/metabolism , Drug Discovery , Protease Inhibitors/chemistry , Tartrates/chemistry , Tumor Necrosis Factor-alpha/metabolism , ADAM17 Protein , Binding Sites , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Discovery/methods , Humans , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Tartrates/metabolism , Tartrates/pharmacologyABSTRACT
The present paper describes a novel series of HCV RNA polymerase inhibitors based on a pyrazolo[1,5-a]pyrimidine scaffold bearing hydrophobic groups and an acidic functionality. Several compounds were optimized to low nanomolar potencies in a biochemical RdRp assay. SAR trends clearly reveal a stringent preference for a cyclohexyl group as one of the hydrophobes, and improved activities for carboxylic acid derivatives.
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hepatitis C/enzymology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , RNA, Viral/drug effects , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Evaluation, Preclinical , Hepacivirus , Hepatitis C/virology , Inhibitory Concentration 50 , Molecular Weight , Small Molecule LibrariesABSTRACT
A series of 4H-pyrazolo[1,5-a]pyrimidin-7-one derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase. A number of these compounds exhibited potent activity in enzymatic assay. The synthesis and structure-activity relationship are also described.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/enzymology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Antiviral Agents/chemistry , Models, Molecular , Protein Binding , Pyrazoles/chemistry , Pyrimidines/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , Structure-Activity RelationshipABSTRACT
Aminothiazole-based inhibitors designed for HCV polymerase display low micromolar potencies in biochemical assays. These compounds show a stringent preference for a cyclohexyl hydrophobe at the 2-amino position. The composition of these compounds suggests that they may be interacting at a recently discovered allosteric site on the polymerase.
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Thiazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Thiazoles/chemical synthesisABSTRACT
Several Bacillus strains belonging to the B. subtilis/amyloliquefaciens group isolated from plant-pathogen-infested soil possess plant-growth-promoting activity [Krebs, B. et al. (1998) J Plant Dis Prot 105, 181-197]. Three out of the four strains investigated were identified as B. amyloliquefaciens and were able to degrade extracellular phytate (myo-inositol hexakisphosphate). The highest extracellular phytase activity was detected in strain FZB45, and diluted culture filtrates of this strain stimulated growth of maize seedlings under phosphate limitation in the presence of phytate. The amino acid sequence deduced from the phytase phyA gene cloned from FZB45 displayed a high degree of similarity to known Bacillus phytases. Weak similarity between FZB45 phytase and B. subtilis alkaline phosphatase IV pointed to a possible common origin of these two enzymes. The recombinant protein expressed by B. subtilis MU331 displayed 3(1)-phytase activity yielding D/L-Ins(1,2,4,5,6)P5 as the first product of phytate hydrolysis. A phytase-negative mutant strain, FZB45/M2, whose phyA gene is disrupted, was generated by replacing the entire wild-type gene on the chromosome of FZB45 with a km::phyA fragment, and culture filtrates obtained from FZB45/M2 did not stimulate plant growth. In addition, the growth of maize seedlings was promoted in the presence of purified phytase and the absence of culture filtrate. These genetic and biochemical experiments provide strong evidence that phytase activity of B. amyloliquefaciens FZB45 is important for plant growth stimulation under phosphate limitation.
