ABSTRACT
Physicochemical properties, such as solubility, are important when prioritising compounds for progression on a drug discovery project. There is limited literature around the systematic effects of core changes on thermodynamic solubility. This work details the synthesis of nitrogen containing 6,5-bicyclic heterocyclic cores which are common scaffolds in medicinal chemistry and the analysis of their physicochemical properties, particularly, thermodynamic solubility. Crystalline solids were obtained where possible to enable a robust comparison of the thermodynamic solubility. Other parameters such as pKa, melting point and lipophilicity were also measured to determine the key factors affecting the observed solubility.
Subject(s)
Amides/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Nitrogen/chemistry , Pyrimidines/chemistry , Thermodynamics , Amides/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemical synthesis , Molecular Structure , Pyrimidines/chemical synthesis , SolubilityABSTRACT
The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIß is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations.
ABSTRACT
Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Sulfonamides/pharmacology , Animals , Crystallography, X-Ray , Female , Male , Mice, Inbred BALB C , Molecular Structure , Phosphoinositide-3 Kinase Inhibitors/chemical synthesis , Phosphoinositide-3 Kinase Inhibitors/metabolism , Protein Binding , Rats, Wistar , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolismABSTRACT
A novel pyrrole-2-carboxamide series of p38alpha inhibitors, discovered through the application of virtual screening, is presented. Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series' suitability for further lead optimisation studies.
Subject(s)
Amides/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrroles/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Dose-Response Relationship, Drug , High-Throughput Screening Assays , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class III Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/pharmacokinetics , Animals , Binding, Competitive , Biological Availability , Cell Membrane Permeability , Crystallography, X-Ray , Drug Discovery , Humans , Isoenzymes , Models, Molecular , Molecular Docking Simulation , Phosphoinositide-3 Kinase Inhibitors/toxicity , Rats , Structure-Activity RelationshipABSTRACT
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Structure-Activity Relationship , Administration, Inhalation , Animals , Class Ia Phosphatidylinositol 3-Kinase/chemistry , Crystallography, X-Ray , Dogs , Drug Evaluation, Preclinical , ERG1 Potassium Channel/metabolism , Enzyme Inhibitors/administration & dosage , Hydrogen Bonding , Isoquinolines/chemistry , Madin Darby Canine Kidney Cells , RatsABSTRACT
We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.
ABSTRACT
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Subject(s)
Indazoles/chemistry , Oxazoles/chemistry , Phosphoinositide-3 Kinase Inhibitors , Respiratory Tract Diseases/drug therapy , Sulfonamides/chemistry , Administration, Inhalation , Animals , Asthma/drug therapy , Female , Humans , Indazoles/pharmacokinetics , Indazoles/pharmacology , Indoles , Isoenzymes/antagonists & inhibitors , Male , Microsomes/metabolism , Molecular Docking Simulation , Ovalbumin/immunology , Oxazoles/pharmacokinetics , Oxazoles/pharmacology , Piperazines , Pneumonia/drug therapy , Pneumonia/immunology , Pulmonary Disease, Chronic Obstructive/drug therapy , Rabbits , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Th2 Cells/immunologyABSTRACT
The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.