ABSTRACT
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.
Subject(s)
Inflammation/drug therapy , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Administration, Oral , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Imidazoles/pharmacology , Inflammation/enzymology , Interleukin-1 Receptor-Associated Kinases/metabolism , Interleukin-6/antagonists & inhibitors , Interleukin-6/biosynthesis , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Quinazolines/administration & dosage , Quinazolines/chemistry , Rats , Rats, Inbred Lew , Structure-Activity RelationshipABSTRACT
IRAK4 plays a critical role in the IL-1R and TLR signalling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by cLogD led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Carboxylic Acids/chemistry , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Amides/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Cyclization , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/pharmacologyABSTRACT
Starting from compound 1, we utilized biostructural data to successfully evolve an existing series into a new chemotype with a promising overall profile, exemplified by 19.
Subject(s)
Drug Design , Indans/chemistry , Indans/pharmacology , Receptors, AMPA/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Allosteric Regulation , Animals , Cell Line , Crystallography, X-Ray , Humans , Indans/metabolism , Indans/pharmacokinetics , Microsomes, Liver/metabolism , Models, Molecular , Nervous System Diseases/drug therapy , Nervous System Diseases/metabolism , Pyrazoles/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , Sulfonamides/metabolism , Sulfonamides/pharmacokineticsABSTRACT
The detection of low affinity interactions between proteins and ligands by biophysical methods is challenging. It is often necessary to use competition methods that are time consuming and require well characterized known binders. A mass spectrometry approach is presented for identifying low affinity protein-ligand binding which does not require direct detection of the parent protein-ligand complex but depends on characteristic changes observed in the protein mass spectrum. We observe that on titration of ligand there are characteristic 'charge-state shifts' which manifest as changes in the relative intensities of protein peaks that correlate with the degree of protein-ligand complex formation. We suggest that use of this phenomenon will be particularly suitable for the identification of low affinity complexes where the intensity of any complex ion would be close to noise.
Subject(s)
Spectrometry, Mass, Electrospray Ionization , Tacrolimus Binding Protein 1A/chemistry , DNA, Recombinant/chemistry , DNA, Recombinant/genetics , Humans , Ligands , Protein Binding , Tacrolimus Binding Protein 1A/geneticsABSTRACT
Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.
Subject(s)
Indazoles/chemistry , Receptors, AMPA/chemistry , Thiophenes/chemistry , Allosteric Regulation , Animals , Binding Sites , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Indazoles/chemical synthesis , Indazoles/pharmacology , Microsomes/metabolism , Protein Structure, Tertiary , Rats , Receptors, AMPA/metabolism , Thiophenes/chemical synthesis , Thiophenes/pharmacologyABSTRACT
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.
Subject(s)
Amines/chemistry , Amines/pharmacology , Drug Design , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptors, AMPA/metabolism , Allosteric Regulation , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Biological Availability , Crystallography, X-Ray , Humans , Models, Molecular , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Rats , Rats, Wistar , Receptors, AMPA/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propioic acid (AMPA) subtype of glutamate receptors mediate fast excitatory neurotransmission throughout the mammalian nervous system and participate in the forms of synaptic plasticity that are considered to underlie learning and memory. Positive allosteric modulators of these receptors are the subject of much investigation because of their emerging therapeutic potential for a range of psychiatric and neurological disorders such as schizophrenia and Alzheimer's disease. This review focuses on the most recent developments in preclinical and clinical research on novel classes of AMPA receptor positive modulators and highlights how the application of biostructural studies has increased our understanding of the biophysical effects produced by these drugs.
Subject(s)
Receptors, AMPA/antagonists & inhibitors , Animals , Humans , Models, Molecular , Receptors, AMPA/agonists , Receptors, AMPA/chemistry , Receptors, AMPA/physiology , Structure-Activity RelationshipABSTRACT
The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAF(V600E) xenograft model.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Urea/analogs & derivatives , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Mice , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacologyABSTRACT
Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.
ABSTRACT
Phosphopantetheine adenylyltransferase (PPAT) is an essential enzyme in Coenzyme A biosynthesis. Because bacterial PPAT and mammalian PPAT are dissimilar, this enzyme is an attractive antibacterial target. Based on the structure of the substrate, 4-phosphopantetheine, a dipeptide library was designed, synthesised and tested against Escherichia coli PPAT. The most potent inhibitor PTX040334 was co-crystallised with E. coli PPAT. With this structural information, a rational iterative medicinal chemistry program was initiated, aimed at increasing the number of inhibitor-enzyme interactions. A very potent and specific inhibitor, PTX042695, with an IC(50) of 6 nM against E.coli PPAT, but with no activity against porcine PPAT, was obtained.
Subject(s)
Dipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Nucleotidyltransferases/antagonists & inhibitors , Coenzyme A/biosynthesis , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Escherichia coli/drug effects , Escherichia coli/enzymology , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Nucleotidyltransferases/metabolismABSTRACT
Positive allosteric modulators of α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors facilitate synaptic plasticity and can improve various forms of learning and memory. These modulators show promise as therapeutic agents for the treatment of neurological disorders such as schizophrenia, ADHD, and mental depression. Three classes of positive modulator, the benzamides, the thiadiazides, and the biarylsulfonamides differentially occupy a solvent accessible binding pocket at the interface between the two subunits that form the AMPA receptor ligand-binding pocket. Here, we describe the electrophysiological properties of a new chemotype derived from a structure-based drug design strategy (SBDD), which makes similar receptor interactions compared to previously reported classes of modulator. This pyrazole amide derivative, JAMI1001A, with a promising developability profile, efficaciously modulates AMPA receptor deactivation and desensitization of both flip and flop receptor isoforms. This article is part of a Special Issue entitled 'Cognitive Enhancers'.