RESUMO
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.
Assuntos
Proteínas Tirosina Quinases , Transdução de Sinais , Quinase Syk , Inibidores de Proteínas Quinases/farmacologiaRESUMO
ROS1 rearrangements account for 1-2% of non-small cell lung cancer patients, yet there are no specifically designed, selective ROS1 therapies in the clinic. Previous knowledge of potent ROS1 inhibitors with selectivity over TrkA, a selected antitarget, enabled virtual screening as a hit finding approach in this project. The ligand-based virtual screening was focused on identifying molecules with a similar 3D shape and pharmacophore to the known actives. To that end, we turned to the AstraZeneca virtual library, estimated to cover 1015 synthesizable make-on-demand molecules. We used cloud computing-enabled FastROCS technology to search the enumerated 1010 subset of the full virtual space. A small number of specific libraries were prioritized based on the compound properties and a medicinal chemistry assessment and further enumerated with available building blocks. Following the docking evaluation to the ROS1 structure, the most promising hits were synthesized and tested, resulting in the identification of several potent and selective series. The best among them gave a nanomolar ROS1 inhibitor with over 1000-fold selectivity over TrkA and, from the preliminary established SAR, these have the potential to be further optimized. Our prospective study describes how conceptually simple shape-matching approaches can identify potent and selective compounds by searching ultralarge virtual libraries, demonstrating the applicability of such workflows and their importance in early drug discovery.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Computação em Nuvem , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Estudos Prospectivos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina QuinasesRESUMO
Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group. The initial compound 5 achieved excellent SYK potency. However, it suffered from poor permeability and modest kinase selectivity. Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinase Syk/antagonistas & inibidores , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Quinase Syk/metabolismoRESUMO
BACKGROUND/AIMS: LRRK2 (leucine-rich repeat protein kinase 2) is one of the most commonly accepted genes associated with Parkinson's disease (PD). The overexpression of disease-associated mutations in LRRK2 is toxic to the cells, while reduction or elimination of LRRK2 expression promotes cell health and growth. Thus, the identification of an LRRK2 inhibitor with good physiochemical and pharmacokinetic properties is of great interest for the treatment of PD. METHODS: In this study, we have investigated LRRK2 compounds, LRRK2-IN-1 and Compound 1, in vitro and in vivo to determine how suitable they are as a selective LRRK2 tool compound. RESULTS: We report that Compound 1, patented by GSK, is a potent and selective LRRK2 inhibitor with good blood-brain barrier permeability as reflected by its high brain to plasma ratio in rats. In addition, Compound 1 can significantly promote neurite outgrowth in a primary cortical culture, indicating an optimistic cellular function of this compound in a biological system. In contrast, LRRK2-IN-1 is a less selective LRRK2 inhibitor and has low brain penetration. Furthermore, LRRK2-IN-1 is cyto- and genotoxic, while Compound 1 does not exhibit any toxicity. CONCLUSIONS: These results suggest that Compound 1 may be a superior tool compound than LRRK2-IN-1 to advance future pharmacological research on LRRK2.
Assuntos
Benzodiazepinonas/farmacologia , Descoberta de Drogas/métodos , Doença de Parkinson/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/sangue , Benzodiazepinonas/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Doença de Parkinson/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/genética , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/farmacocinética , Ratos Sprague-Dawley , Especificidade por Substrato , Distribuição TecidualRESUMO
The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.
Assuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Compostos Organofosforados/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos Nus , Camundongos SCID , Mutação , Compostos Organofosforados/síntese química , Compostos Organofosforados/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The identification of novel orally active mGluR5 antagonist GSK2210875 is described.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Administração Oral , Regulação Alostérica , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Camundongos , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.
Assuntos
Encéfalo/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Encéfalo/metabolismoRESUMO
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported.
Assuntos
Imidazolidinas/química , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Gatos , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Imidazolidinas/síntese química , Imidazolidinas/farmacologia , Ligantes , Receptores de Dopamina D3/metabolismo , Relação Estrutura-AtividadeRESUMO
A new class of selective MMP-12 inhibitors have been identified via high throughput screening. Crystallization with MMP-12 confirmed the mode of binding and allowed initial optimization to be carried out using classical structure based design.
Assuntos
Ácidos Carboxílicos/química , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Animais , Sítios de Ligação , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Cobaias , Humanos , Metaloproteinase 12 da Matriz/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
Selective leads: In this study, we generated a new series of serotonin 5-HT7 receptor antagonists. Their synthesis, structure-activity relationships, and selectivity profiles are reported. This series includes 5-HT7 antagonists with unprecedented high selectivity for the 5-HT7 receptor, setting the stage for lead optimization of drugs acting on a range of neurological targets.
Assuntos
Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/química , Antagonistas da Serotonina/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Células HEK293 , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A high-throughput screen targeting the EP(1) receptor identified non-acidic glycine sulfonamide derivative 2a with a pK(i) of 6.2. Analogue synthesis allowed a thorough investigation of the structure-activity relationship (SAR) and led to a 100-fold increase in recombinant potency.
Assuntos
Glicinérgicos/síntese química , Glicinérgicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Células CHO , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Cricetinae , Cricetulus , Sistema Enzimático do Citocromo P-450/metabolismo , Dinoprostona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Indicadores e Reagentes , Receptores de Prostaglandina E Subtipo EP1RESUMO
The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.