ABSTRACT
We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.
Subject(s)
Aniline Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Quinazolines/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-ret/metabolism , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity RelationshipABSTRACT
Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Quinazolines/chemistry , Quinazolines/pharmacology , Animals , Cell Line , Drug Design , Humans , Mice , Molecular Docking Simulation , Piperidines/pharmacokinetics , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-ret/metabolism , Quinazolines/pharmacokineticsABSTRACT
Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay were identified, and this improved activity translated to efficacy in a cellular assay. The SAR for steroid inhibition of G6PD has been substantially developed; the 3ß-alcohol can be replaced with 3ß-H-bond donors such as sulfamide, sulfonamide, urea, and carbamate. Improved potency was achieved by replacing the androstane nucleus with a pregnane nucleus, provided a ketone at C-20 is present. For pregnan-20-ones incorporation of a 21-hydroxyl group is often beneficial. The novel compounds generally have good physicochemical properties and satisfactory in vitro DMPK parameters. These derivatives may be useful for examining the role of G6PD inhibition in cells and will assist the future design of more potent steroid inhibitors with potential therapeutic utility.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glucosephosphate Dehydrogenase/antagonists & inhibitors , Pregnanes/chemistry , Pregnanes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Survival/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Glucosephosphate Dehydrogenase/metabolism , HEK293 Cells , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mass Spectrometry , Pregnanes/chemical synthesis , Pregnanes/pharmacokinetics , Structure-Activity RelationshipABSTRACT
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
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.