RESUMO
Managed pressure drilling (MPD) is the most effective means to ensure drilling safety, and MPD is able to avoid further deterioration of complex working conditions through precise control of the wellhead back pressure. The key to the success of MPD is the well control strategy, which currently relies heavily on manual experience, hindering the automation and intelligence process of well control. In response to this issue, an MPD knowledge graph is constructed in this paper that extracts knowledge from published papers and drilling reports to guide well control. In order to improve the performance of entity extraction in the knowledge graph, a few-shot Chinese entity recognition model CEntLM-KL is extended from the EntLM model, in which the KL entropy is built to improve the accuracy of entity recognition. Through experiments on benchmark datasets, it has been shown that the proposed model has a significant improvement compared to the state-of-the-art methods. On the few-shot drilling datasets, the F-1 score of entity recognition reaches 33%. Finally, the knowledge graph is stored in Neo4J and applied for knowledge inference.
RESUMO
A series of benzodiazepine antagonists of the human ghrelin receptor GHSR1a were synthesized and their antagonism and metabolic stability were evaluated. The potency of these analogs was determined using a functional aequorin (Euroscreen) luminescent assay measuring the intracellular Ca(2+) concentration, and their metabolic stability was measured using an in vitro rat and human S9 hepatocyte assay. These efforts led to the discovery of a potent ghrelin antagonist with good rat pharmacokinetic properties.
Assuntos
Benzodiazepinas/química , Benzodiazepinas/farmacologia , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/metabolismo , Animais , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Cálcio/metabolismo , Linhagem Celular , Hepatócitos/metabolismo , Humanos , Medições Luminescentes , Obesidade/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Antagonists of adenosine receptor are under exploration as potential drug candidates for treatment of neurological disorders, depression, certain cancers and potentially used as a cancer immunotherapy. Herein, we describe design and synthesis of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine (6) derivatives. All the compounds were evaluated for A2A AR antagonist activity and displayed encouraging results (IC50 9-300 nM) of A2A AR antagonist binding affinity in biochemical assay. Compound 27 exhibits good activity in A2A AR antagonist cAMP functional assay (IC50 31 nM) and further this compound shows T-cell activation at the IL-2 production assay (EC50 165 nM). Molecular docking studies were carried out to rationalize the observed binding affinity of compound 27.
Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Desenho de Fármacos , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The discovery and parallel synthesis of potent, small molecule antagonists of Neuromedin B receptor based on the ary-hexahydro-dibenzodiazepin-1-one core is described.
Assuntos
Benzodiazepinonas/síntese química , Química Farmacêutica/métodos , Receptores da Bombesina/antagonistas & inibidores , Animais , Benzodiazepinonas/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Elétrons , Peptídeo Liberador de Gastrina/química , Células HeLa , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Peptídeos/química , Relação Estrutura-AtividadeRESUMO
A new series of pyrazolo[3,4-d]pyrimidine-3,6-diamines was designed and synthesized as potent and selective inhibitors of the nonreceptor tyrosine kinase, ACK1. These compounds arose from efforts to rigidify an earlier series of N-aryl pyrimidine-5-carboxamides. The synthesis and structure-activity relationships of this new series of inhibitors are reported. The most promising compounds were also profiled for their pharmacokinetic properties.
Assuntos
Diaminas/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/química , Pirimidinas/química , Animais , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Masculino , Modelos Químicos , Conformação Molecular , Proteínas Tirosina Quinases/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.
Assuntos
Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Quinases/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Inibidores Enzimáticos/química , Humanos , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Acoplados a Proteínas G/antagonistas & inibidoresRESUMO
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Descoberta de Drogas , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antineoplásicos/química , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismoRESUMO
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Morfolinas/síntese química , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/química , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Indicadores e Reagentes , Camundongos , Modelos Moleculares , Conformação Molecular , Morfolinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.
RESUMO
We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Ácidos Carboxílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Piperidonas/farmacologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Animais , Neoplasias Ósseas/tratamento farmacológico , Ácidos Carboxílicos/química , Células Cultivadas , Cristalografia por Raios X , Desenho de Fármacos , Feminino , Humanos , Ligação de Hidrogênio , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Osteossarcoma/tratamento farmacológico , Piperidonas/química , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Piperidonas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Administração Oral , Antineoplásicos/química , Disponibilidade Biológica , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Piperidonas/química , Conformação ProteicaRESUMO
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.