RÉSUMÉ
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.
Sujet(s)
Adénomes/diagnostic , Tumeurs du côlon/diagnostic , Formation médicale continue comme sujet/méthodes , Gastro-entérologues/enseignement et éducation , Anatomopathologistes/enseignement et éducation , Adénomes/épidémiologie , Adénomes/anatomopathologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Californie , Études de cohortes , Tumeurs du côlon/épidémiologie , Tumeurs du côlon/anatomopathologie , Coloscopie/méthodes , Centres de santé communautaires , Femelle , Humains , Mâle , Adulte d'âge moyen , Études rétrospectivesRÉSUMÉ
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.
Sujet(s)
Adénosine triphosphate/métabolisme , Fixation compétitive , Découverte de médicament , Inhibiteurs de protéines kinases/métabolisme , Inhibiteurs de protéines kinases/pharmacologie , Sérine-thréonine kinases TOR/antagonistes et inhibiteurs , Sérine-thréonine kinases TOR/métabolisme , Administration par voie orale , Animaux , Benzoxazines/composition chimique , Benzoxazines/métabolisme , Benzoxazines/pharmacocinétique , Benzoxazines/pharmacologie , Biodisponibilité , Lignée cellulaire tumorale , Chiens , Femelle , Humains , Mâle , Souris , Modèles moléculaires , Conformation des protéines , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacocinétique , Rats , Spécificité du substrat , Sérine-thréonine kinases TOR/composition chimiqueRÉSUMÉ
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.
Sujet(s)
Antinéoplasiques/pharmacologie , Kinase Janus-2/antagonistes et inhibiteurs , Tumeurs expérimentales/traitement médicamenteux , Proline/analogues et dérivés , Inhibiteurs de protéines kinases/pharmacologie , Pyrimidines/pharmacologie , Animaux , Antinéoplasiques/administration et posologie , Antinéoplasiques/composition chimique , Apoptose/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cristallographie aux rayons X , Chiens , Relation dose-effet des médicaments , Haplorhini , Tests de criblage à haut débit , Kinase Janus-2/métabolisme , Souris , Souris nude , Modèles moléculaires , Structure moléculaire , Tumeurs expérimentales/anatomopathologie , Proline/administration et posologie , Proline/composition chimique , Proline/pharmacologie , Inhibiteurs de protéines kinases/administration et posologie , Inhibiteurs de protéines kinases/composition chimique , Pyrimidines/administration et posologie , Pyrimidines/composition chimique , Rats , Relation structure-activité , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
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.
Sujet(s)
Antinéoplasiques/synthèse chimique , Récepteurs aux lysosphingolipides/antagonistes et inhibiteurs , Administration par voie orale , Amides/synthèse chimique , Amides/pharmacocinétique , Amides/pharmacologie , Inhibiteurs de l'angiogenèse/synthèse chimique , Inhibiteurs de l'angiogenèse/pharmacocinétique , Inhibiteurs de l'angiogenèse/pharmacologie , Dérivés de l'aniline/synthèse chimique , Dérivés de l'aniline/pharmacocinétique , Dérivés de l'aniline/pharmacologie , Animaux , Antinéoplasiques/pharmacocinétique , Antinéoplasiques/pharmacologie , Biodisponibilité , Lignée cellulaire , Prolifération cellulaire/effets des médicaments et des substances chimiques , Chiens , Haplorhini , Tests de criblage à haut débit , Souris , Néovascularisation pathologique , Proline/analogues et dérivés , Proline/synthèse chimique , Proline/pharmacocinétique , Proline/pharmacologie , Rats , Sérine/analogues et dérivés , Sérine/synthèse chimique , Sérine/pharmacocinétique , Sérine/pharmacologie , Stéréoisomérie , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
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.
Sujet(s)
Anticoagulants/synthèse chimique , Anticoagulants/pharmacologie , Benzamides/synthèse chimique , Benzamides/pharmacologie , Découverte de médicament/méthodes , Inhibiteurs du facteur Xa , Pyridines/synthèse chimique , Pyridines/pharmacologie , Administration par voie orale , Animaux , Anticoagulants/administration et posologie , Benzamides/administration et posologie , Domaine catalytique/effets des médicaments et des substances chimiques , Lignée cellulaire , Chiens , Relation dose-effet des médicaments , Canal potassique ERG1 , Canaux potassiques éther-à-go-go/génétique , Facteur Xa/métabolisme , Humains , Macaca fascicularis , Pyridines/administration et posologie , Lapins , RatsRÉSUMÉ
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.
Sujet(s)
Antinéoplasiques/pharmacologie , Transformation cellulaire néoplasique , Mutation , Inhibiteurs de protéines kinases/pharmacologie , Quinazolines/pharmacologie , Récepteur ErbB-2/antagonistes et inhibiteurs , Récepteur ErbB-2/génétique , Survie cellulaire , Résistance aux médicaments antinéoplasiques , Humains , Lapatinib , Phosphorylation , Conformation des protéines , Récepteur ErbB-2/composition chimiqueRÉSUMÉ
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.
Sujet(s)
Antithrombine-III/synthèse chimique , Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Inhibiteurs du facteur Xa , Antithrombine-III/pharmacologie , Antienzymes/composition chimique , Humains , Conformation moléculaire , Structure moléculaire , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Benzamidines/pharmacologie , Inhibiteurs du facteur Xa , Inhibiteurs de la sérine protéinase/pharmacologie , Benzamidines/composition chimique , Benzamidines/pharmacocinétique , Biodisponibilité , Inhibiteurs de la sérine protéinase/composition chimique , Inhibiteurs de la sérine protéinase/pharmacocinétiqueRÉSUMÉ
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.
Sujet(s)
Amides/synthèse chimique , Amides/pharmacologie , Inhibiteurs du facteur Xa , ortho-Aminobenzoates/synthèse chimique , ortho-Aminobenzoates/pharmacologie , Administration par voie orale , Animaux , Biodisponibilité , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Conception de médicament , Humains , Structure moléculaire , Lapins , Rats , Rat Sprague-Dawley , Relation structure-activité , Thrombose/traitement médicamenteuxRÉSUMÉ
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.
Sujet(s)
Amides/synthèse chimique , Antithrombine-III/synthèse chimique , Benzamidines/antagonistes et inhibiteurs , Pyrazoles/synthèse chimique , Administration par voie orale , Amides/administration et posologie , Amides/métabolisme , Animaux , Antithrombine-III/administration et posologie , Antithrombine-III/métabolisme , Benzamidines/métabolisme , Biodisponibilité , Conception de médicament , Humains , Pyrazoles/administration et posologie , Pyrazoles/métabolisme , Rats , Rat Sprague-Dawley , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Inhibiteurs du facteur Xa , Pipérazines/synthèse chimique , Inhibiteurs de la sérine protéinase/synthèse chimique , Anticoagulants/synthèse chimique , Anticoagulants/composition chimique , Sites de fixation , Conception de médicament , Humains , Concentration inhibitrice 50 , Modèles moléculaires , Conformation moléculaire , Pipérazines/composition chimique , Pipérazines/pharmacologie , Inhibiteurs de la sérine protéinase/composition chimique , Inhibiteurs de la sérine protéinase/pharmacologie , Relation structure-activité , Thrombine/antagonistes et inhibiteursRÉSUMÉ
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.
Sujet(s)
Inhibiteurs du facteur Xa , Oxazines/synthèse chimique , Oxazines/pharmacologie , Dérivés de l'aniline/synthèse chimique , Dérivés de l'aniline/pharmacologie , Animaux , Fixation compétitive/effets des médicaments et des substances chimiques , Cristallographie aux rayons X , Relation dose-effet des médicaments , Conception de médicament , Techniques in vitro , Indicateurs et réactifs , Modèles moléculaires , Conformation moléculaire , Lapins , Relation structure-activité , Thrombine/métabolisme , Inhibiteurs trypsiques/synthèse chimique , Inhibiteurs trypsiques/pharmacologieRÉSUMÉ
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.
Sujet(s)
Inhibiteurs du facteur Xa , Pyrazoles/synthèse chimique , Pyrazoles/pharmacologie , Inhibiteurs de la sérine protéinase/synthèse chimique , Inhibiteurs de la sérine protéinase/pharmacologie , Amides/composition chimique , Animaux , Conception de médicament , Pyrazoles/composition chimique , Pyrazoles/pharmacocinétique , Rats , Inhibiteurs de la sérine protéinase/composition chimique , Inhibiteurs de la sérine protéinase/pharmacocinétique , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Benzamidines/synthèse chimique , Benzamidines/pharmacologie , Inhibiteurs du facteur Xa , Isoquinoléines/synthèse chimique , Isoquinoléines/pharmacologie , Inhibiteurs de la sérine protéinase/synthèse chimique , Inhibiteurs de la sérine protéinase/pharmacologie , Administration par voie orale , Animaux , Benzamidines/composition chimique , Benzamidines/pharmacocinétique , Biodisponibilité , Conception de médicament , Isoquinoléines/composition chimique , Isoquinoléines/pharmacocinétique , Rats , Rat Sprague-Dawley , Inhibiteurs de la sérine protéinase/composition chimique , Inhibiteurs de la sérine protéinase/pharmacocinétique , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Conception de médicament , Antienzymes/composition chimique , Inhibiteurs de protéines kinases , Techniques de chimie combinatoire , Conception assistée par ordinateur , Antienzymes/pharmacologie , Humains , Ligands , Modèles moléculaires , Relation quantitative structure-activitéRÉSUMÉ
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.
Sujet(s)
Acrylamides/synthèse chimique , Acrylamides/pharmacologie , Antithrombine-III/synthèse chimique , Antithrombine-III/pharmacologie , Inhibiteurs du facteur Xa , Acrylamides/composition chimique , Animaux , Antithrombine-III/composition chimique , Sites de fixation , Biodisponibilité , Modèles animaux de maladie humaine , Conception de médicament , Ligands , Modèles moléculaires , Lapins , Rats , Stéréoisomérie , Relation structure-activité , Matrices (génétique) , Thrombose/traitement médicamenteuxRÉSUMÉ
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.