RESUMO
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.
Assuntos
Cicloeptanos/química , Cicloeptanos/farmacologia , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Animais , Broncoconstrição/efeitos dos fármacos , Cicloeptanos/farmacocinética , Modelos Animais de Doenças , Cobaias , Humanos , Estrutura Molecular , Antagonistas Muscarínicos/farmacocinética , Receptores Muscarínicos/química , Receptores Muscarínicos/metabolismoRESUMO
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.
Assuntos
Antagonistas Muscarínicos/química , Piperidinas/química , Quinuclidinas/química , Receptor Muscarínico M3/agonistas , Proteínas Sanguíneas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ligação Proteica , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/farmacologia , Quinuclidinas/uso terapêutico , Receptor Muscarínico M3/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Permeabilidade da Membrana Celular , Complexo I de Transporte de Elétrons/deficiência , Doenças Mitocondriais/metabolismo , Pró-Fármacos/farmacologia , Ácido Succínico/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Fibroblastos/patologia , Humanos , Lactatos/metabolismo , Doença de Leigh/patologia , Metabolômica , Modelos Biológicos , Pró-Fármacos/química , Ácido Succínico/químicaRESUMO
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.
Assuntos
Catepsina C/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Humanos , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Proteínas Recombinantes/química , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Especificidade por Substrato , Difração de Raios XRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Indazóis/síntese química , Indazóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Cobre/química , Hidrocarbonetos Cíclicos/síntese química , Modelos Químicos , Modelos Moleculares , Estrutura MolecularRESUMO
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.