ABSTRACT
The isomers of dibenzylamino-1-methylcyclohexan-1-ol and dibenzylamino-1-trifluoromethylcyclohexan-1-ol have been prepared. The stereochemistry of these compounds was unequivocally assigned through a combination of NMR spectroscopy and single crystal X-ray analysis. The cis-isomer of 3-N,N-dibenzylamino-1-trifluoromethylcyclohexanol and its derivatives display an unusual conformational behaviour in both solution-phase and the solid-state, where the amino group usually adopts an axial conformation.
Subject(s)
Benzylamines/chemical synthesis , Cyclohexanols/chemical synthesis , Benzylamines/chemistry , Crystallography, X-Ray , Cyclohexanols/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.
Subject(s)
Drug Design , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Algorithms , Databases, Factual , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Ligands , Lipids/chemistry , Molecular Structure , SolubilityABSTRACT
Machine learning approaches promise to accelerate and improve success rates in medicinal chemistry programs by more effectively leveraging available data to guide a molecular design. A key step of an automated computational design algorithm is molecule generation, where the machine is required to design high-quality, drug-like molecules within the appropriate chemical space. Many algorithms have been proposed for molecular generation; however, a challenge is how to assess the validity of the resulting molecules. Here, we report three Turing-inspired tests designed to evaluate the performance of molecular generators. Profound differences were observed between the performance of molecule generators in these tests, highlighting the importance of selection of the appropriate design algorithms for specific circumstances. One molecule generator, based on match molecular pairs, performed excellently against all tests and thus provides a valuable component for machine-driven medicinal chemistry design workflows.
Subject(s)
Algorithms , Machine Learning , Chemistry, Pharmaceutical , Drug Design , Humans , Molecular StructureABSTRACT
The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
Subject(s)
High-Throughput Screening Assays/methods , Proteins/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Chemokine CCL2/biosynthesis , Crystallography, X-Ray , Drug Discovery , Drug Evaluation, Preclinical , Drug Synergism , Humans , Interleukin-6/antagonists & inhibitors , Leukocytes/drug effects , Male , Mice , Models, Molecular , Protein Processing, Post-Translational/drug effects , Small Molecule LibrariesABSTRACT
Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
Subject(s)
Phosphodiesterase 4 Inhibitors , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/chemistry , Quinolines/administration & dosage , Quinolines/chemistry , Administration, Oral , Animals , Cattle , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Humans , Male , Protein Structure, Secondary , Protein Structure, Tertiary , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.
Subject(s)
Chemistry, Pharmaceutical/methods , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Phosphodiesterase 4 Inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Benzamides/pharmacology , Crystallography, X-Ray/methods , Cyclopropanes/pharmacology , Drug Design , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Models, Biological , Models, Chemical , Pyrrolidinones/chemistry , Rats , Rolipram/pharmacology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
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
A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Respiratory Tract Diseases/drug therapy , Administration, Inhalation , Animals , Biological Availability , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Dose-Response Relationship, Drug , Male , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Rats , Rats, Sprague-Dawley , Respiratory Tract Diseases/metabolism , Structure-Activity RelationshipABSTRACT
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
In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.
Subject(s)
Chemistry, Pharmaceutical/education , Drug Design , Drug Discovery/methods , Curriculum , Drug Industry/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Models, Molecular , Phosphoinositide-3 Kinase Inhibitors , SolubilityABSTRACT
REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.
Subject(s)
Amines/chemical synthesis , Nuclear Receptor Subfamily 1, Group D, Member 1/agonists , Amines/chemistry , Amines/pharmacology , Animals , Biological Availability , Carrier Proteins/metabolism , Cell Line , Circadian Rhythm , Glycine/analogs & derivatives , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Humans , Liver X Receptors , Mice , Mice, Inbred C57BL , Orphan Nuclear Receptors/metabolism , Peptide Fragments/metabolism , RNA-Binding Proteins , Radioligand Assay , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
Triphenylphosphine tagged with a short poly-(ethyleneglycol)-ω-monomethyl ether chain (light MPEG, 10−16 ethylenoxy units, (M)TPP-G2) and an MPEG-tagged version of diethyl azodicarboxylate ((M)DEAD) have been used to prepare a 20 member library of esters, ethers, and sulfonamides, with cLogP's in the range of 1.4−5.7 on a 0.1 mmol scale. Removal of MPEG-tagged side products was achieved by MPEG-assisted solid-phase extraction (MSPE) on prepacked silica columns to give the products in good yield and high purity.
Subject(s)
Combinatorial Chemistry Techniques , Molecular Weight , Solid Phase ExtractionABSTRACT
Neighborhood behavior describes the extent to which small structural changes defined by a molecular descriptor are likely to lead to small property changes. This study evaluates two methods for the quantification of neighborhood behavior: the optimal diagonal method of Patterson et al. and the optimality criterion method of Horvath and Jeandenans. The methods are evaluated using twelve different types of fingerprint (both 2D and 3D) with screening data derived from several lead optimization projects at GlaxoSmithKline. The principal focus of the work is the design of chemical arrays during lead optimization, and the study hence considers not only biological activity but also important drug properties such as metabolic stability, permeability, and lipophilicity. Evidence is provided to suggest that the optimality criterion method may provide a better quantitative description of neighborhood behavior than the optimal diagonal method.
Subject(s)
Drug Design , PermeabilityABSTRACT
2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.