ABSTRACT
Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [(13)C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction.
Subject(s)
Cell Membrane Permeability , Electron Transport Complex I/deficiency , Mitochondrial Diseases/metabolism , Prodrugs/pharmacology , Succinic Acid/pharmacology , Cell Membrane Permeability/drug effects , Cell Respiration/drug effects , Drug Discovery , Drug Evaluation, Preclinical , Electron Transport Complex I/metabolism , Electron Transport Complex II/metabolism , Fibroblasts/pathology , Humans , Lactates/metabolism , Leigh Disease/pathology , Metabolomics , Models, Biological , Prodrugs/chemistry , Succinic Acid/chemistryABSTRACT
A lead generation and optimization program delivered the highly selective and potent CatC inhibitor 10 as an in vivo tool compound and potential development candidate. Structural studies were undertaken to generate SAR understanding.
Subject(s)
Cathepsin C/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Humans , Indicators and Reagents , Models, Molecular , Molecular Conformation , Recombinant Proteins/chemistry , Spectrometry, Fluorescence , Structure-Activity Relationship , Substrate Specificity , X-Ray DiffractionABSTRACT
A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.
Subject(s)
Cycloheptanes/chemistry , Cycloheptanes/pharmacology , Muscarinic Antagonists/administration & dosage , Muscarinic Antagonists/chemistry , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Animals , Bronchoconstriction/drug effects , Cycloheptanes/pharmacokinetics , Disease Models, Animal , Guinea Pigs , Humans , Molecular Structure , Muscarinic Antagonists/pharmacokinetics , Receptors, Muscarinic/chemistry , Receptors, Muscarinic/metabolismABSTRACT
The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD.
Subject(s)
Muscarinic Antagonists/chemistry , Piperidines/chemistry , Quinuclidines/chemistry , Receptor, Muscarinic M3/agonists , Blood Proteins/metabolism , Drug Evaluation, Preclinical , Humans , Muscarinic Antagonists/pharmacology , Muscarinic Antagonists/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Protein Binding , Pulmonary Disease, Chronic Obstructive/drug therapy , Quinuclidines/pharmacology , Quinuclidines/therapeutic use , Receptor, Muscarinic M3/metabolism , Structure-Activity RelationshipABSTRACT
The design and synthesis of a new series of c-Jun N-terminal kinase inhibitors are reported. The novel series of substituted amino indazoles were designed based on a combination of hits from high-throughput screening and X-ray crystal structure information of the compounds crystallised into the JNK-1 ATP binding site.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Indazoles/chemical synthesis , Indazoles/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Binding Sites , Crystallography, X-Ray , Drug Design , JNK Mitogen-Activated Protein Kinases/metabolism , Mitogen-Activated Protein Kinase 8/antagonists & inhibitors , Mitogen-Activated Protein Kinase 8/metabolism , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Simple organocopper reagents are shown to undergo anti-stereoselective 1,4-addition to menthyloxy-substituted lactone 1 in the presence of BF3.OEt2; the Lewis acid causes partial epimerisation of the acetal centre after conjugate addition. Enolate alkylation of the adducts leads to di- and trisubstituted lactones that are converted, in favourable cases, into di- and trisubstituted cyclopentenones.
Subject(s)
Copper/chemistry , Hydrocarbons, Cyclic/chemical synthesis , Models, Chemical , Models, Molecular , Molecular StructureABSTRACT
Chemical double mutant cycles have been used to quantify the interactions of halogens with the faces of aromatic rings in chloroform. The halogens are forced over the face of an aromatic ring by an array of hydrogen-bonding interactions that lock the complexes in a single, well-defined conformation. These interactions can also be engineered into the crystal structures of simpler model compounds, but experiments in solution show that the halogen-aromatic interactions observed in the solid state are all unfavourable, regardless of whether the aromatic rings contain electron-withdrawing or electron-donating substituents. The halogen-aromatic interactions are repulsive by 1-3 kJ mol(-1). The interactions with fluorine are slightly less favourable than with chlorine and bromine.
