ABSTRACT
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.
Subject(s)
MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Binding, Competitive , Cells, Cultured , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Discovery , Enzyme Activation/drug effects , Humans , Kinetics , MAP Kinase Kinase 2/metabolism , Magnetic Resonance Spectroscopy , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Mitogen-Activated Protein Kinase 14/chemistry , Mitogen-Activated Protein Kinase 14/metabolism , Models, Chemical , Models, Molecular , Molecular Structure , Phosphorylation/drug effects , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 90-kDa/chemistry , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Structure-Activity Relationship , Substrate Specificity , Surface Plasmon ResonanceABSTRACT
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Subject(s)
Down-Regulation/drug effects , Drug Discovery , Prostatic Neoplasms/drug therapy , Pyridazines/pharmacology , Receptors, Androgen/metabolism , Small Molecule Libraries/pharmacology , Animals , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Molecular Structure , Prostatic Neoplasms/pathology , Pyridazines/chemical synthesis , Pyridazines/chemistry , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex.
Subject(s)
Cathepsin L/antagonists & inhibitors , Cathepsin L/chemistry , Nitriles/chemical synthesis , Animals , Cartilage, Articular/pathology , Catalysis , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Humans , Ligands , Mice , Mice, Transgenic , Nitriles/chemistry , Nitriles/pharmacology , Peptides/chemical synthesis , Peptides/pharmacology , Proteins/chemistry , Structure-Activity RelationshipABSTRACT
A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.