ABSTRACT
4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).
Subject(s)
Bridged Bicyclo Compounds/chemistry , Cycloheptanes/chemistry , Morpholines/chemistry , Phosphatidylinositol 3-Kinases , Phosphoinositide-3 Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Bridged Bicyclo Compounds/pharmacology , Cycloheptanes/pharmacology , Drug Discovery/methods , Humans , Morpholines/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolismABSTRACT
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
Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.
Subject(s)
Analgesics/chemistry , Calcium Channel Blockers/chemistry , Calcium Channels/chemistry , Neuralgia/drug therapy , Pyrazoles/chemistry , Pyridazines/chemistry , Pyridines/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Analgesics/chemical synthesis , Analgesics/therapeutic use , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/therapeutic use , Calcium Channels/metabolism , Calcium Channels, L-Type , Ligands , Pyrazoles/chemical synthesis , Pyridazines/chemical synthesis , Pyridazines/therapeutic use , Pyridines/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
We report the identification of a novel biaryl template for H(+)/K(+) ATPase inhibition. Evaluation of critical SAR features within the biaryl imidazole framework and the use of pharmacophore modelling against known imidazopyridine and azaindole templates suggested that the geometry of the molecule is key to achieving activity. Herein we present our work optimising the potency of the molecule through modifications and substitutions to each of the ring systems. In particular sub-micromolar potency is achieved with (4b) presumably through a proposed intramolecular hydrogen bond that ensures the required imidazole basic centre is appropriately located.
Subject(s)
Drug Discovery/methods , Imidazoles/chemistry , Proton Pump Inhibitors , H(+)-K(+)-Exchanging ATPase/metabolism , Imidazoles/metabolism , Imidazoles/pharmacology , Structure-Activity RelationshipABSTRACT
A systematic analysis of data generated in key in vitro assays within GSK has been undertaken to identify what impact a range of common substituents have on a range of ADMET parameters. These include; P450 1A2, 2C9, 2C19, 2D6 and 3A4 inhibition, hERG inhibition, phosphate buffer solubility and artificial membrane permeability. We do this by identifying all matched molecular pairs, differing by the replacement of a hydrogen atom with a list of predefined substituents. For each substituent we calculate the mean difference in the ADMET parameter for all the matched molecular pairs identified, making a statistical assessment of the difference, as well as assessing the diversity for each example to ensure that the results can be generalized. We also relate the change in activity observed for each substituent to differences in their molecular properties in an effort to identify any structural alerts.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Drug Design , Pharmaceutical Preparations/chemistry , Cell Membrane Permeability , Combinatorial Chemistry Techniques , Cytochrome P-450 Enzyme System/metabolism , Drug Industry , Drug-Related Side Effects and Adverse Reactions , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Pharmaceutical Preparations/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
Three field-based similarity methods are compared in retrospective virtual screening experiments. The methods are the CatShape module of CATALYST, ROCS, and an in-house program developed at the University of Sheffield called FBSS. The programs are used in both rigid and flexible searches carried out in the MDL Drug Data Report. UNITY 2D fingerprints are also used to provide a comparison with a more traditional approach to similarity searching, and similarity based on simple whole-molecule properties is used to provide a baseline for the more sophisticated searches. Overall, UNITY 2D fingerprints and ROCS with the chemical force field option gave comparable performance and were superior to the shape-only 3D methods. When the flexible methods were compared with the rigid methods, it was generally found that the flexible methods gave slightly better results than their respective rigid methods; however, the increased performance did not justify the additional computational cost required.
ABSTRACT
Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Pyrrolidines/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Biological Availability , Chlorocebus aethiops , Hepacivirus/enzymology , Models, Molecular , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , RNA-Dependent RNA Polymerase/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Vero CellsABSTRACT
Three commercially available pharmacophore generation programs, Catalyst/HipHop, DISCO and GASP, were compared on their ability to generate known pharmacophores deduced from protein-ligand complexes extracted from the Protein Data Bank. Five different protein families were included Thrombin, Cyclin Dependent Kinase 2, Dihydrofolate Reductase, HIV Reverse Transcriptase and Thermolysin. Target pharmacophores were defined through visual analysis of the data sets. The pharmacophore models produced were evaluated qualitatively through visual inspection and according to their ability to generate the target pharmacophores. Our results show that GASP and Catalyst outperformed DISCO at reproducing the five target pharmacophores.