Sujet(s)
Dermatoses faciales/traitement médicamenteux , Leishmania tropica , Leishmaniose cutanée/traitement médicamenteux , Maladies du nez/traitement médicamenteux , Photothérapie dynamique , Adulte , Acide amino-lévulinique/analogues et dérivés , Acide amino-lévulinique/usage thérapeutique , Dermatoses faciales/parasitologie , Humains , Mâle , Maladies du nez/parasitologie , Photosensibilisants/usage thérapeutiqueRÉSUMÉ
In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.
Sujet(s)
Antiviraux/pharmacologie , Antienzymes/pharmacologie , Hepacivirus/effets des médicaments et des substances chimiques , Quinoléines/pharmacologie , Sulfonamides/pharmacologie , Protéines virales non structurales/antagonistes et inhibiteurs , Animaux , Antiviraux/composition chimique , Antiviraux/pharmacocinétique , Chiens , Découverte de médicament , Antienzymes/composition chimique , Antienzymes/pharmacocinétique , Hepacivirus/enzymologie , Humains , Modèles moléculaires , Quinoléines/composition chimique , Quinoléines/pharmacocinétique , Rats , Sulfonamides/composition chimique , Sulfonamides/pharmacocinétiqueRÉSUMÉ
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Sujet(s)
JNK Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Pyrimidines/composition chimique , Pyrimidines/pharmacologie , Triazoles/composition chimique , Triazoles/pharmacologie , Animaux , Cristallographie aux rayons X , Conception de médicament , Humains , JNK Mitogen-Activated Protein Kinases/métabolisme , Modèles moléculaires , Inhibiteurs de protéines kinases/synthèse chimique , Pyrimidines/synthèse chimique , Rats , Relation structure-activité , Triazoles/synthèse chimiqueRÉSUMÉ
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Sujet(s)
Conception de médicament , Activation enzymatique/effets des médicaments et des substances chimiques , Antienzymes/synthèse chimique , Antienzymes/pharmacologie , Mitogen-Activated Protein Kinase 14/antagonistes et inhibiteurs , Pyrimidines/synthèse chimique , Pyrimidines/pharmacologie , Animaux , Cristallographie aux rayons X , Antienzymes/composition chimique , Concentration inhibitrice 50 , Modèles moléculaires , Structure moléculaire , Pyrazoles/synthèse chimique , Pyrazoles/composition chimique , Pyrazoles/pharmacologie , Pyrimidines/composition chimique , RatsRÉSUMÉ
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
Sujet(s)
Découverte de médicament/méthodes , Mitogen-Activated Protein Kinase 14/antagonistes et inhibiteurs , Pyridones/pharmacologie , Pyridones/pharmacocinétique , Pyrimidines/pharmacologie , Pyrimidines/pharmacocinétique , Administration par voie orale , Polyarthrite rhumatoïde/traitement médicamenteux , Biodisponibilité , Lignée cellulaire , Essais cliniques comme sujet , Humains , Mitogen-Activated Protein Kinase 14/composition chimique , Modèles moléculaires , Conformation des protéines , Inhibiteurs de protéines kinases/administration et posologie , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacocinétique , Inhibiteurs de protéines kinases/pharmacologie , Pyridones/administration et posologie , Pyridones/composition chimique , Pyrimidines/administration et posologie , Pyrimidines/composition chimique , Relation structure-activité , Spécificité du substratRÉSUMÉ
Elaboration of our previously disclosed spiropiperidine template led to the development of a series of novel CCR5 antagonists. Results of SAR exploration and preliminary lead characterization are described.
Sujet(s)
Antagonistes des récepteurs CCR5 , Imidazolidines/synthèse chimique , Imidazolidines/pharmacologie , Animaux , Lignée cellulaire , Évaluation préclinique de médicament , Humains , Imidazolidines/composition chimique , Imidazolidines/pharmacocinétique , Rats , Relation structure-activitéRÉSUMÉ
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Sujet(s)
Agents antiVIH/composition chimique , Benzamides/composition chimique , Antagonistes des récepteurs CCR5 , Inhibiteurs de fusion du VIH/composition chimique , Pyrroles/composition chimique , Animaux , Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacocinétique , Benzamides/synthèse chimique , Benzamides/pharmacologie , Inhibiteurs de fusion du VIH/synthèse chimique , Inhibiteurs de fusion du VIH/pharmacocinétique , Humains , Microsomes du foie/métabolisme , Pyrroles/synthèse chimique , Pyrroles/pharmacocinétique , Rats , Récepteurs CCR5/métabolisme , Relation structure-activitéRÉSUMÉ
Acetaminophen-induced liver toxicity is the most frequent precipitating cause of acute liver failure and liver transplant, but contemporary medical practice has mainly focused on patient management after a liver injury has been induced. An integrative genetic, transcriptional, and two-dimensional NMR-based metabolomic analysis performed using multiple inbred mouse strains, along with knowledge-based filtering of these data, identified betaine-homocysteine methyltransferase 2 (Bhmt2) as a diet-dependent genetic factor that affected susceptibility to acetaminophen-induced liver toxicity in mice. Through an effect on methionine and glutathione biosynthesis, Bhmt2 could utilize its substrate (S-methylmethionine [SMM]) to confer protection against acetaminophen-induced injury in vivo. Since SMM is only synthesized in plants, Bhmt2 exerts its beneficial effect in a diet-dependent manner. Identification of Bhmt2 and the affected biosynthetic pathway demonstrates how a novel method of integrative genomic analysis in mice can provide a unique and clinically applicable approach to a major public health problem.
Sujet(s)
Acétaminophène/effets indésirables , Analgésiques non narcotiques/effets indésirables , Betaine-homocysteine S-methyltransferase/génétique , Lésions hépatiques dues aux substances/génétique , Défaillance hépatique aigüe/génétique , Vitamine U/métabolisme , Acétaminophène/métabolisme , Acétaminophène/pharmacocinétique , Animaux , Betaine-homocysteine S-methyltransferase/métabolisme , Lésions hépatiques dues aux substances/étiologie , Lésions hépatiques dues aux substances/anatomopathologie , Lésions hépatiques dues aux substances/prévention et contrôle , Régime alimentaire , Analyse de profil d'expression de gènes , Foie/métabolisme , Foie/anatomopathologie , Défaillance hépatique aigüe/induit chimiquement , Défaillance hépatique aigüe/anatomopathologie , Défaillance hépatique aigüe/prévention et contrôle , Spectroscopie par résonance magnétique , Souris , Lignées consanguines de souris , Données de séquences moléculaires , Séquençage par oligonucléotides en batterie , Analyse de séquence d'ADNRÉSUMÉ
A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed.
Sujet(s)
Antagonistes des récepteurs CCR5 , Pipéridines/composition chimique , Pipéridines/pharmacologie , Récepteurs CCR5/métabolisme , Animaux , Cellules Caco-2 , Chiens , Haplorhini , Humains , Pipéridines/pharmacocinétique , Rats , Spiranes/composition chimique , Spiranes/pharmacocinétique , Spiranes/pharmacologie , Relation structure-activitéRÉSUMÉ
The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C(ub)), cerebral spinal fluid concentration (C(CSF)), and unbound plasma concentration (C(up)) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C(m)). Nine compounds-carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental-were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1-9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the C(ub)s were within 3-fold of their C(m); thiopental had a C(m) 4-fold of its C(ub). The C(CSF)s of eight of the nine compounds were within 3-fold of their corresponding C(m); 9-hydroxyrisperidone showed a C(CSF) 5-fold of its C(m). The C(up)s of five of the nine compounds were within 3-fold of their C(m); four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had C(up)s 6- to 14-fold of their C(m). In conclusion, the C(ub) and C(CSF) were within 3-fold of the C(m) for the majority of the compounds tested. The C(up)s were within 3-fold of C(m) for lipophilic non-P-glycoprotein (-P-gp) substrates and greater than 3-fold of C(m) for hydrophilic or P-gp substrates. The present study indicates that the brain homogenate and cerebral spinal fluid methods may be used as surrogate methods to predict brain interstitial fluid concentrations within 3-fold of error in drug discovery and development settings.
Sujet(s)
Encéphale/métabolisme , Liquide extracellulaire/métabolisme , Préparations pharmaceutiques/métabolisme , Animaux , Chromatographie en phase liquide à haute performance , Mâle , Microdialyse , Préparations pharmaceutiques/liquide cérébrospinal , Rats , Rat Sprague-Dawley , Spectrométrie de masse en tandemRÉSUMÉ
Combining the experimental efficiency of a murine hepatic in vitro drug biotransformation system with in silico genetic analysis produces a model system that can rapidly analyze interindividual differences in drug metabolism. This model system was tested by using two clinically important drugs, testosterone and irinotecan, whose metabolism was previously well characterized. The metabolites produced after these drugs were incubated with hepatic in vitro biotransformation systems prepared from the 15 inbred mouse strains were measured. Strain-specific differences in the rate of 16 alpha-hydroxytestosterone generation and irinotecan glucuronidation correlated with the pattern of genetic variation within Cyp2b9 and Ugt1a loci, respectively. These computational predictions were experimentally confirmed using expressed recombinant enzymes. The genetic changes affecting irinotecan metabolism in mice mirrored those in humans that are known to affect the pharmacokinetics and incidence of adverse responses to this medication.
Sujet(s)
Souris/génétique , Pharmacogénétique/méthodes , Testostérone/métabolisme , Animaux , Aryl hydrocarbon hydroxylases/génétique , Aryl hydrocarbon hydroxylases/métabolisme , Biotransformation , Cytochrome P-450 enzyme system/génétique , Cytochrome P-450 enzyme system/métabolisme , Famille-2 de cytochromes P450 , Glucuronosyltransferase/génétique , Glucuronosyltransferase/métabolisme , Foie/enzymologie , Foie/métabolisme , Préparations pharmaceutiques/métabolisme , Protéines recombinantes/métabolisme , Steroid hydroxylases/génétique , Steroid hydroxylases/métabolisme , Testostérone/analogues et dérivésRÉSUMÉ
Analysis of mouse genetic models of human disease-associated traits has provided important insight into the pathogenesis of human disease. As one example, analysis of a murine genetic model of osteoporosis demonstrated that genetic variation within the 15-lipoxygenase (Alox15) gene affected peak bone mass, and that treatment with inhibitors of this enzyme improved bone mass and quality in rodent models. However, the method that has been used to analyze mouse genetic models is very time consuming, inefficient, and costly. To overcome these limitations, a computational method for analysis of mouse genetic models was developed that markedly accelerates the pace of genetic discovery. It was used to identify a genetic factor affecting the rate of metabolism of warfarin, an anticoagulant that is commonly used to treat clotting disorders. Computational analysis of a murine genetic model of narcotic drug withdrawal suggested a potential new approach for treatment of narcotic drug addiction. Thus, the results derived from computational mouse genetic analysis can suggest new treatment strategies, and can provide new information about currently available medicines.
Sujet(s)
Biologie informatique , Génome , Préparations pharmaceutiques , Locus de caractère quantitatif , Animaux , Évaluation préclinique de médicament , Variation génétique , Haplotypes , Souris , Modèles génétiquesRÉSUMÉ
Pharmacogenetic approaches can be instrumental for predicting individual differences in response to a therapeutic intervention. Here we used a recently developed murine haplotype-based computational method to identify a genetic factor regulating the metabolism of warfarin, a commonly prescribed anticoagulant with a narrow therapeutic index and a large variation in individual dosing. After quantification of warfarin and nine of its metabolites in plasma from 13 inbred mouse strains, we correlated strain-specific differences in 7-hydroxywarfarin accumulation with genetic variation within a chromosomal region encoding cytochrome P450 2C (Cyp2c) enzymes. This computational prediction was experimentally confirmed by showing that the rate-limiting step in biotransformation of warfarin to its 7-hydroxylated metabolite was inhibited by tolbutamide, a Cyp2c isoform-specific substrate, and that this transformation was mediated by expressed recombinant Cyp2c29. We show that genetic variants responsible for interindividual pharmacokinetic differences in drug metabolism can be identified by computational genetic analysis in mice.
Sujet(s)
Pharmacogénétique/méthodes , Warfarine/pharmacologie , Animaux , Biotransformation , Cartographie chromosomique , Cytochrome P-450 enzyme system/génétique , Variation génétique , Haplotypes , Mâle , Souris , Lignées consanguines de souris , Isoformes de protéines , Spécificité d'espèce , Warfarine/métabolismeRÉSUMÉ
A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.
Sujet(s)
Anti-inflammatoires/synthèse chimique , Pyrazoles/synthèse chimique , p38 Mitogen-Activated Protein Kinases/antagonistes et inhibiteurs , Adénosine triphosphate/composition chimique , Administration par voie orale , Animaux , Anti-inflammatoires/composition chimique , Anti-inflammatoires/pharmacologie , Arthrite expérimentale/traitement médicamenteux , Sites de fixation , Biodisponibilité , Lignée cellulaire , Cristallographie aux rayons X , Chiens , Femelle , Haplorhini , Humains , Interleukine-1/antagonistes et inhibiteurs , Interleukine-1/biosynthèse , Interleukine-6/antagonistes et inhibiteurs , Interleukine-6/biosynthèse , Modèles moléculaires , Pyrazoles/composition chimique , Pyrazoles/pharmacologie , Rats , Rats de lignée LEW , Stéréoisomérie , Relation structure-activité , Facteur de nécrose tumorale alpha/antagonistes et inhibiteurs , p38 Mitogen-Activated Protein Kinases/composition chimiqueRÉSUMÉ
It is generally anticipated that pharmacogenomic information will have a large impact on drug development and will facilitate individualized drug treatment. However, there has been relatively little quantitative modeling to assess how pharmacogenomic information could be best utilized in clinical practice. Using a quantitative model, this review demonstrates that efficacy is increased and toxicity is reduced when a genetically-guided dose adjustment strategy is utilized in a clinical trial. However, there is limited information available regarding the genetic variables affecting the disposition or mechanism of action of most commonly used medications. These genetic factors must be identified to enable pharmacogenomic testing to be routinely used in the clinic. A recently described murine haplotype-based computational genetic analysis method provides one strategy for identifying genetic factors regulating the pharmacokinetics and pharmacodynamics of commonly used medications.
Sujet(s)
Pharmacogénétique/tendances , Pharmacologie/tendances , Animaux , Conception de médicament , Humains , Modèles génétiques , Préparations pharmaceutiques/administration et posologieRÉSUMÉ
Fungating nodules and infiltrated plaques are usually equated with advanced tumor stage mycosis fungoides. We report an 85-year-old man who presented in this way but multiple skin biopsies revealed that the bulk of his nodules were due to marked follicular hyperplasia as a result of folliculotropic mycosis fungoides. This clinical presentation may be best described as a pseudotumorous form of mycosis fungoides dominated by follicular epithelial hyperplasia rather than lymphocytic proliferation characteristic of true tumor stage disease. Similar presentations have been described as a verrucous and hyperplastic variant of mycosis fungoides due to the presence of prominent epidermal hyperplasia.
Sujet(s)
Follicule pileux/anatomopathologie , Mycosis fongoïde/anatomopathologie , Tumeurs cutanées/anatomopathologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Follicule pileux/métabolisme , Humains , Hyperplasie/métabolisme , Hyperplasie/anatomopathologie , Immunohistochimie , Mâle , Mycosis fongoïde/métabolisme , Tumeurs cutanées/métabolismeRÉSUMÉ
The aim of this study was to determine the remaining dentin thickness (RDT) in the apical 4 mm following four cleaning and shaping techniques. Sixty human adult extracted mandibular incisors and 60 mesial buccal canals of mandibular molars were assigned to five groups of 12 teeth for each tooth type: Step-down stainless steel hand instrumentation, Lightspeed, Profile GT and 0.4 taper, K3 "g pack," control group. After instrumentation the teeth were sectioned at 0.5, 1.5, 2.5, and 3.5 mm short of working length (WL) and evaluated for the minimum RDT at each level. ANOVA of RDT showed significant differences among levels and techniques. For incisors, no technique yielded greater RDT than the other techniques (p < 0.0001). For molars, K3 had greater RDT than the other techniques (p = 0.0006) at the 1.5, 2.5, and 3.5 mm levels. While there were significant statistical differences in RDT among techniques at different levels, further study would be required to determine any significant clinical difference in RDT.
Sujet(s)
Instruments dentaires , Dentine/anatomie et histologie , Préparation de canal radiculaire/instrumentation , Préparation de canal radiculaire/méthodes , Apex de la racine de la dent/anatomie et histologie , Adulte , Analyse de variance , Cavité pulpaire de la dent/anatomie et histologie , Humains , Incisive , Mandibule , MolaireRÉSUMÉ
The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.