RESUMO
A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo N/metabolismo , Neuralgia/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Descoberta de Drogas , Células HEK293 , Humanos , Masculino , Neuralgia/metabolismo , Técnicas de Patch-Clamp , Piranos/química , Piranos/farmacologia , Piranos/uso terapêutico , Pirazóis/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Pirróis/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
A novel series of 2-thio-5-thiomethyl substituted imidazoles was discovered to be potent TGR5 agonists that possessed glucose-lowering effects while inhibiting gall bladder emptying in mice.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Esvaziamento da Vesícula Biliar/efeitos dos fármacos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Imidazóis/química , Imidazóis/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Humanos , Hipoglicemiantes/farmacologia , Imidazóis/farmacologia , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas G/metabolismoRESUMO
A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Disponibilidade Biológica , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Células HEK293 , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Camundongos Endogâmicos C57BL , Fenilpropionatos/farmacocinética , Fenilpropionatos/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery of a novel series of cyclopenta[b]furans as CCR2 inhibitors is discussed. This series has excellent CCR2 potency and PK characteristics, and good cardiovascular safety.
Assuntos
Furanos/química , Furanos/farmacologia , Receptores CCR2/antagonistas & inibidores , Linhagem Celular , Quimiocina CCL2/imunologia , Humanos , Receptores CCR2/imunologiaRESUMO
SAR study of 5-aminooctahydrocyclopentapyrrole-3a-carboxamide scaffold led to identification of several CCR2 antagonists with potent activity in both binding and functional assays. Their cardiovascular safety and pharmacokinetic properties were also evaluated.
Assuntos
Ciclopentanos/farmacologia , Descoberta de Drogas , Pirróis/farmacologia , Receptores CCR2/antagonistas & inibidores , Ciclopentanos/síntese química , Ciclopentanos/química , Relação Dose-Resposta a Droga , Humanos , Conformação Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
A novel series of substituted tetrahydropyrrolo[3,4-c]pyrazoles were investigated as blockers of the N-type calcium channel (Cav2.2 channels), a chronic pain target.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/metabolismo , Dor Crônica/tratamento farmacológico , Humanos , Microssomos Hepáticos/metabolismo , Pirazóis/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
A novel series of substituted 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles were investigated as N-type calcium channel blockers (Cav2.2 channels), a chronic pain target. One compound was active in vivo in the rat CFA pain model.
Assuntos
Analgésicos/química , Analgésicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Analgésicos/metabolismo , Analgésicos/farmacocinética , Animais , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacocinética , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Pirazóis/metabolismo , Pirazóis/farmacocinética , RatosRESUMO
Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed.
Assuntos
Amidas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclopentanos/química , Piridinas/química , Receptores CCR2/antagonistas & inibidores , Administração Oral , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Modelos Animais de Doenças , Cães , Meia-Vida , Haplorrinos , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Knockout , Ligação Proteica , Piridinas/farmacocinética , Piridinas/uso terapêutico , Receptores CCR2/genética , Receptores CCR2/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The inflammatory response associated with the activation of C-C chemokine receptor CCR2 via it's interaction with the monocyte chemoattractant protein-1 (MCP-1, CCL2) has been implicated in many disease states, including rheumatoid arthritis, multiple sclerosis, atherosclerosis, asthma and neuropathic pain. Small molecule antagonists of CCR2 have been efficacious in animal models of inflammatory disease, and have been advanced into clinical development. The necessity to attenuate hERG binding appears to be a common theme for many of the CCR2 antagonist scaffolds appearing in the literature, presumably due the basic hydrophobic motif present in all of these molecules. Following the discovery of a novel cyclohexyl azetidinylamide CCR2 antagonist scaffold, replacement of the amide bond with heterocyclic rings was explored as a strategy for reducing hERG binding and improving pharmacokinetic properties.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Azetidinas/química , Azetidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Animais , Humanos , CamundongosRESUMO
Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.
Assuntos
Analgésicos/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/metabolismo , Dor Crônica/tratamento farmacológico , Neuralgia/tratamento farmacológico , Piperidinas/síntese química , Pirazóis/síntese química , Analgésicos/uso terapêutico , Animais , Bloqueadores dos Canais de Cálcio/uso terapêutico , Linhagem Celular , Dor Crônica/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Neuralgia/metabolismo , Técnicas de Patch-Clamp , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Relação Estrutura-Atividade , ômega-Conotoxinas/uso terapêuticoRESUMO
This paper focused on adding a suitable lubrication effect at the interface between the rubber and mixer chamber wall on reducing the surface wear rate of the mixer chamber wall. In the research process, the contact model between the compound and internal mixer chamber wall was simplified to the pin-on-disc experimental model. The experimental results showed that the friction coefficient and the metal surface wear rate of the mixer chamber were reduced (by approximately 24%) by adding an appropriate amount of antifriction agent in the mixing process, while the comprehensive properties of the compound showed an improvement trend. By analyzing the surface elements of the rubber compound, the MoS2 with an anti-wear effect on the surface of the rubber compound can form a lubrication mechanism between the rubber, filler, and mixer chamber wall metal. Combined with the result of the comprehensive properties of rubber, which showed that although the appropriate amount of antifriction agent formed a lubrication protection mechanism between the rubber and the inner mixing chamber wall, the mechanism did not affect the friction behavior required for mixing. The study can effectively enhance the effective friction mixing and reduce the wear and power consumption of the mixing chamber caused by excess friction during the mixing process.
RESUMO
Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).
Assuntos
Metionina Adenosiltransferase , Neoplasias , Encéfalo/metabolismo , Desenho de Fármacos , Humanos , Neoplasias/tratamento farmacológico , S-Adenosilmetionina/metabolismoRESUMO
A novel series of 4-azetidinyl-1-aryl-cyclohexanes containing indazole or benzoisoxazole moiety have been identified as potent CCR2 antagonists with high selectivity versus hERG.
Assuntos
Indazóis/química , Indazóis/farmacologia , Oxazóis/química , Oxazóis/farmacologia , Receptores CCR2/antagonistas & inibidores , Animais , Linhagem Celular , Cicloexanos/síntese química , Cicloexanos/química , Cicloexanos/farmacocinética , Cicloexanos/farmacologia , Cães , Desenho de Fármacos , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Oxazóis/síntese química , Oxazóis/farmacocinética , Ratos , Receptores CCR2/metabolismo , Relação Estrutura-Atividade , Transativadores/metabolismo , Regulador Transcricional ERGRESUMO
A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties.
Assuntos
Descoberta de Drogas , Frutoquinases/antagonistas & inibidores , Indazóis/farmacologia , Pirazóis/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Indazóis/síntese química , Indazóis/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG.
Assuntos
Azetidinas/farmacologia , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Hipuratos/farmacologia , Receptores CCR2/antagonistas & inibidores , Azetidinas/síntese química , Azetidinas/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Hipuratos/síntese química , Hipuratos/química , Humanos , Estrutura Molecular , Receptores CCR2/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation.
Assuntos
Amidas/química , Anti-Inflamatórios/química , Receptores CCR2/antagonistas & inibidores , Doença Aguda , Administração Oral , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Ratos , Receptores CCR2/metabolismo , Relação Estrutura-AtividadeRESUMO
The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10â¯000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).
Assuntos
Inibidores Enzimáticos/química , Metionina Adenosiltransferase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/genética , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Homozigoto , Humanos , Metionina Adenosiltransferase/metabolismo , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Purina-Núcleosídeo Fosforilase/metabolismo , S-Adenosilmetionina/metabolismo , Relação Estrutura-AtividadeRESUMO
The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.