RESUMO
BACKGROUND AND AIMS: Sessile serrated adenomas (SSAs) are precursors of 15% to 30% of colorectal cancers but are frequently underdiagnosed. We sought to measure the SSA detection rate (SDR) and predictors of SSA detection after educational training for community gastroenterologists and pathologists. METHODS: Colonoscopy and pathology data (2010-2014) from 3 medical centers at Kaiser Permanente Northern California were accessed electronically. Gastroenterologists and pathologists attended a training session on SSA diagnosis in 2012. Mean SDRs and patient-level predictors of SSA detection post-training (2013-2014) were investigated. RESULTS: Mean SDRs increased from .6% in 2010-2012 to 3.7% in 2013-2014. The increase in the detection of proximal SSAs was accompanied by a decrease in the detection of proximal hyperplastic polyps (HPs). Among 34,161 colonoscopies performed in 2013 to 2014, SDRs for screening, fecal immunochemical test positivity, surveillance, and diagnostic indication were 4.2%, 4.5%, 4.9%, and 3.0%, respectively. SSA detection was lower among Asians (adjusted odds ratio [aOR], .46; 95% confidence interval [CI], .31-.69) and Hispanics (aOR, .59; 95% CI, .36-.95) compared with non-Hispanic whites and higher among patients with synchronous conventional adenoma (aOR, 1.46; 95% CI, 1.15-1.86), HP (aOR, 1.74; 95% CI, 1.30-2.34), and current smokers (aOR, 1.78; 95% CI, 1.17-2.72). SDRs varied widely among experienced gastroenterologists, even after training (1.1%-8.1%). There was a moderately strong correlation between adenoma detection rate (ADR) and SDR for any SSA (r = .64, P = .0003) and for right-sided SSAs (r = .71, P < .0001). CONCLUSIONS: Educational training significantly increased the detection of SSA, but a wide variation in SDR remained across gastroenterologists. SSA detection was inversely associated with Asian and Hispanic race/ethnicity and positively associated with the presence of conventional adenoma, HP, and current smoking. There was a moderately strong correlation between ADR and SDR.
Assuntos
Adenoma/diagnóstico , Neoplasias do Colo/diagnóstico , Educação Médica Continuada/métodos , Gastroenterologistas/educação , Patologistas/educação , Adenoma/epidemiologia , Adenoma/patologia , Idoso , Idoso de 80 Anos ou mais , California , Estudos de Coortes , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/patologia , Colonoscopia/métodos , Centros Comunitários de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.
Assuntos
Trifosfato de Adenosina/metabolismo , Ligação Competitiva , Descoberta de Drogas , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Administração Oral , Animais , Benzoxazinas/química , Benzoxazinas/metabolismo , Benzoxazinas/farmacocinética , Benzoxazinas/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Cães , Feminino , Humanos , Masculino , Camundongos , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Especificidade por Substrato , Serina-Treonina Quinases TOR/químicaRESUMO
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.
Assuntos
Antineoplásicos/farmacologia , Janus Quinase 2/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Prolina/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Ensaios de Triagem em Larga Escala , Janus Quinase 2/metabolismo , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/patologia , Prolina/administração & dosagem , Prolina/química , Prolina/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.
Assuntos
Antineoplásicos/síntese química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cães , Haplorrinos , Ensaios de Triagem em Larga Escala , Camundongos , Neovascularização Patológica , Prolina/análogos & derivados , Prolina/síntese química , Prolina/farmacocinética , Prolina/farmacologia , Ratos , Serina/análogos & derivados , Serina/síntese química , Serina/farmacocinética , Serina/farmacologia , Estereoisomerismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Systematic SAR studies of in vitro factor Xa inhibitory activity around compound 1 were performed by modifying each of the three phenyl rings. A class of highly potent, selective, efficacious and orally bioavailable direct factor Xa inhibitors was discovered. These compounds were screened in hERG binding assays to examine the effects of substitution groups on the hERG channel affinity. From the leading compounds, betrixaban (compound 11, PRT054021) has been selected as the clinical candidate for development.
Assuntos
Anticoagulantes/síntese química , Anticoagulantes/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Descoberta de Drogas/métodos , Inibidores do Fator Xa , Piridinas/síntese química , Piridinas/farmacologia , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Benzamidas/administração & dosagem , Domínio Catalítico/efeitos dos fármacos , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/genética , Fator Xa/metabolismo , Humanos , Macaca fascicularis , Piridinas/administração & dosagem , Coelhos , RatosRESUMO
PURPOSE: Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib. EXPERIMENTAL DESIGN: We did in vitro screening using a randomly mutagenized ErbB2 expression library in Ba/F3 cells, which were dependent on ErbB2 activity for survival and growth. RESULTS: Lapatinib resistance screens identified mutations at 16 different ErbB2 amino acid residues, with 12 mutated amino acids mapping to the kinase domain. Mutations conferring the greatest lapatinib resistance cluster in the NH2-terminal kinase lobe and hinge region. Structural computer modeling studies suggest that lapatinib resistance is caused by multiple mechanisms; including direct steric interference and restriction of conformational flexibility (the inactive state required for lapatinib binding is energetically unfavorable). ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance. ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells, including L755S and T733I mutations known to occur in human breast and gastric carcinomas, supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers. The epidermal growth factor receptor/ErbB2/vascular endothelial growth factor receptor inhibitor EXEL-7647 was found to inhibit almost all lapatinib resistance-associated mutations. Furthermore, no ErbB2 mutations were found to be associated with EXEL-7647 resistance and lapatinib sensitivity. CONCLUSIONS: Taken together, these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects.
Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica , Mutação , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos , Humanos , Lapatinib , Fosforilação , Conformação Proteica , Receptor ErbB-2/químicaRESUMO
Parallel synthesis and iterative optimization led to the discovery of a series of potent and specific factor Xa inhibitors demonstrating excellent in vitro activity with promising pharmacokinetics.
Assuntos
Antitrombina III/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores do Fator Xa , Antitrombina III/farmacologia , Inibidores Enzimáticos/química , Humanos , Conformação Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1 binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been examined.
Assuntos
Benzamidinas/farmacologia , Inibidores do Fator Xa , Inibidores de Serina Proteinase/farmacologia , Benzamidinas/química , Benzamidinas/farmacocinética , Disponibilidade Biológica , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinéticaRESUMO
Compound 2 containing an aminomethylbenzoyl moiety as the S4 binding motif was synthesized in order to modulate hydrophlicity of anthranilamide-based factor Xa inhibitors with substituted biphenyl P4 groups. Structure-activity relationship studies around 2 have led to a series of potent factor Xa inhibitors which are highly active in the human plasma-based thrombin generation assay with 2XTG values less than 1 microM. Compound 55 shows strong antithrombotic activity in our rabbit deep vein thrombosis model, and also exhibits good oral bioavailability and a long half life in rats.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Inibidores do Fator Xa , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Estrutura Molecular , Coelhos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Trombose/tratamento farmacológicoRESUMO
Using N,N-dialkylated benzamidines as the novel P4 motifs, we have designed and synthesized a class of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent and selective fXa inhibitors with significantly improved hydrophilicity and in vitro anticoagulant activity. These benzamidine-P4 fXa inhibitors have displayed excellent oral bioavailability and long half-life.
Assuntos
Amidas/síntese química , Antitrombina III/síntese química , Benzamidinas/antagonistas & inibidores , Pirazóis/síntese química , Administração Oral , Amidas/administração & dosagem , Amidas/metabolismo , Animais , Antitrombina III/administração & dosagem , Antitrombina III/metabolismo , Benzamidinas/metabolismo , Disponibilidade Biológica , Desenho de Fármacos , Humanos , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship of a novel series of substituted piperazinone-based factor Xa inhibitors is described. The most potent compound 34 displays IC(50) of 0.9 nM.
Assuntos
Inibidores do Fator Xa , Piperazinas/síntese química , Inibidores de Serina Proteinase/síntese química , Anticoagulantes/síntese química , Anticoagulantes/química , Sítios de Ligação , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Piperazinas/química , Piperazinas/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Trombina/antagonistas & inibidoresRESUMO
A series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively.
Assuntos
Inibidores do Fator Xa , Oxazinas/síntese química , Oxazinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Técnicas In Vitro , Indicadores e Reagentes , Modelos Moleculares , Conformação Molecular , Coelhos , Relação Estrutura-Atividade , Trombina/metabolismo , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/farmacologiaRESUMO
Based on DuPont Pharmaceuticals' monobenzamidine lead structure SN429, we have designed the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as a novel series of non-basic factor Xa inhibitors. We have discovered that the displacement of the benzamidine moiety with substituted 2-naphthyl structures not only results in highly potent factor Xa inhibitors, but also significantly increases their enzyme specificity and oral bioavailability.
Assuntos
Inibidores do Fator Xa , Pirazóis/síntese química , Pirazóis/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Amidas/química , Animais , Desenho de Fármacos , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-AtividadeRESUMO
Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.
Assuntos
Benzamidinas/síntese química , Benzamidinas/farmacologia , Inibidores do Fator Xa , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Administração Oral , Animais , Benzamidinas/química , Benzamidinas/farmacocinética , Disponibilidade Biológica , Desenho de Fármacos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-AtividadeRESUMO
The recent success of the first FDA-approved small-molecule tyrosine kinase inhibitor Gleevec (STI-571, imatinib mesylate) in the treatment of chronic myelogenous leukemia (CML) has focused attention on the potential therapeutic usefulness of inhibitors of other kinase targets. This review shall highlight recent applications of computational chemistry methods, comprising both ligand-based and structure-based approaches, in the discovery and design of kinase inhibitors. In particular, we will focus on ATP-competitive inhibitors of selected kinase targets of therapeutic importance.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores de Proteínas Quinases , Técnicas de Química Combinatória , Desenho Assistido por Computador , Inibidores Enzimáticos/farmacologia , Humanos , Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-AtividadeRESUMO
Substituted acrylamides were used as templates that bridge P1 and P4 binding elements, resulting in a series of potent (sub-nanomolar) and selective factor Xa inhibitors. In this template, cis-geometry of P1 and P4 ligands is highly preferred. SAR on the substituting groups, as well as on modification of P1 and P4 moieties is described. Compounds in this series show good in vivo efficacy in animal models.
Assuntos
Acrilamidas/síntese química , Acrilamidas/farmacologia , Antitrombina III/síntese química , Antitrombina III/farmacologia , Inibidores do Fator Xa , Acrilamidas/química , Animais , Antitrombina III/química , Sítios de Ligação , Disponibilidade Biológica , Modelos Animais de Doenças , Desenho de Fármacos , Ligantes , Modelos Moleculares , Coelhos , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Moldes Genéticos , Trombose/tratamento farmacológicoRESUMO
Artemisinin (1) is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua L. Because of the effectiveness of Artemisinin in the treatment of drug-resistant Plasmodium falciparum and its rapid clearance of cerebral malaria, development of clinically useful semisynthetic drugs for severe and complicated malaria (artemether, artesunate) was prompt. However, recent reports of fatal neurotoxicity in animals with dihydroartemisinin derivatives such as artemether have spawned a renewed effort to develop nontoxic analogues of artemisinin. In our effort to develop more potent, less neurotoxic agents for the oral treatment of drug-resistant malaria, we utilized comparative molecular field analysis (CoMFA) and hologram QSAR (HQSAR), beginning with a series of 211 artemisinin analogues with known in vitro antimalarial activity. CoMFA models were based on two conformational hypotheses: (a) that the X-ray structure of artemisinin represents the bioactive shape of the molecule or (b) that the hemin-docked conformation is the bioactive form of the drug. In addition, we examined the effect of inclusion or exclusion of racemates in the partial least squares (pls) analysis. Databases derived from the original 211 were split into chiral (n = 157), achiral (n = 34), and mixed databases (n = 191) after leaving out a test set of 20 compounds. HQSAR and CoMFA models were compared in terms of their potential to generate robust QSAR models. The r(2) and q(2) (cross-validated r(2)) were used to assess the statistical quality of our models. Another statistical parameter, the ratio of the standard error to the activity range (s/AR), was also generated. CoMFA and HQSAR models were developed having statistically excellent properties, which also possessed good predictive ability for test set compounds. The best model was obtained when racemates were excluded from QSAR analysis. Thus, CoMFA of the n = 157 database gave excellent predictions with outstanding statistical properties. HQSAR did an outstanding job in statistical analysis and also handled predictions well.