Design and Synthesis of Inhibitors of the E3 Ligase SMAD Specific E3 Ubiquitin Protein Ligase 1 as a Treatment for Lung Remodeling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a devastating rare disease, which despite currently available treatments, still represents a high unmet medical need. Specific E3 ubiquitin protein ligase 1 (SMURF1) is a HECT E3 ligase that ubiquitinates key signaling molecules from the TGFβ/BMP pathways, which are of great relevance in the pathophysiology of PAH. Herein, the design and synthesis of novel potent small-molecule SMURF1 ligase inhibitors are described.

Vermiremediation of allopathic pharmaceutical industry sludge amended with cattle dung employing Eisenia fetida.

The present study aims to vermiremediate allopathic pharmaceutical industry sludge (AS) amended with cattle dung (CD), in different feed mixtures (AS:CD) i.e (AS) 0:100 [Positive control], (AS) 25:75, (AS) 50:50, (AS) 75:25 and (AS) 100:0 [Negative Control] for 180 days using earthworm Eisenia fetida. The earthworms could thrive and grow well up to the AS feed mixture.

Comparing the nutrient changes, heavy metals, and genotoxicity assessment before and after vermicomposting of thermal fly ash using Eisenia fetida.

Fly ash (FA) is available in an unstable state and can be ameliorated by vermicomposting. The different ratios of FA viz (FA, FA, FA, FA, FA, FA) were mixed with another organic waste, i.e.

Ossiculoplasty: A Prospective Study on 50 Patients Using Various Graft Materials.

With large number of grafts available for ossiculoplasty, choice becomes difficult. An ideal graft should be safe, easily available, cost efficient, with good hearing results, uptake and low extrusion rates. The ear nose and throat surgeon is still facing the indecision over type of graft to be selected.

Correction to "Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP Receptor Antagonist for Treatment of Asthma".

[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP Receptor Antagonist for Treatment of Asthma.

Further optimization of an initial DP receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1-pyrrolo[2,3-]pyridin-3-yl)acetic acid (compound , NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

Do We Need to Study Metabolism and Distribution in the Eye: Why, When, and Are We There Yet?

The liver is known to be the principal site of drug metabolism. Depending on the route of administration, especially in cases of topical and local delivery, evaluation of local drug metabolism in extrahepatic tissues is vital to assess fraction of the drug metabolized. This parameter becomes important from the point of view of drug availability or the contribution to overall clearance.

1-Aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats.

The simultaneous effects of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying were evaluated with the test compound 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole(NVS-CRF38), a novel corticotropin releasing factor receptor 1 (CRF1) antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pretreatment of rats with 100 mg/kg oral ABT administered 2 hours before a semisolid caloric test meal markedly delayed gastric emptying. ABT increased stomach weights by 2-fold; this is likely attributable to a prosecretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups.

Preclinical metabolism and pharmacokinetics of NVS-CRF38, a potent and orally bioavailable corticotropin-releasing factor receptor 1 antagonist.

1. The pharmacokinetic properties and metabolism of NVS-CRF38 [7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole], a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist, were determined in vitro and in animals. 2.

Application of a deuterium replacement strategy to modulate the pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole, a novel CRF1 antagonist.

Deuterium isotope effects were evaluated as a strategy to optimize the pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole (NVS-CRF38), a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist. In an attempt to suppress O-demethylation of NVS-CRF38 without losing activity against the CRF1 receptor, the protons at the site of metabolism were replaced with deuterium. For in vitro and in vivo studies, intrinsic primary isotope effects (KH/KD) were determined by the ratio of intrinsic clearance (CLint) obtained for NVS-CRF38 and deuterated NVS-CRF38.

Decrease in cytochrome c oxidase reserve capacity diminishes robustness of Drosophila melanogaster and shortens lifespan.

The phenotypic effects of under- and over-expression of CcO (cytochrome c oxidase) regulatory subunits IV and Vb were examined in Drosophila melanogaster in order to test further the hypothesis that suppression of the activities of mitochondrial ETC (electron-transport chain) oxidoreductases retards the aging process and extends lifespan. Underexpression of both CcO subunits, induced by RNAi, resulted in decreases in the respective mRNA and protein levels, CcO holoenzyme activity, rate of mitochondrial respiration, walking speed and the lifespan of fruitflies. Overexpression of CcO IV or Vb in young fruitflies increased the amount of mRNA, but had no effect on the protein level or CcO catalytic activity.

Clinico-pathological study of 50 cases of tumours of larynx.

Unlabelled: The larynx serves to protect the lower airways, facilitates respiration and plays a key role in phonation. Based on anatomic location, the larynx is divided into the supraglottic larynx, the glottis or glottic larynx, and the subglottic larynx. The tumours of larynx can be divided into benign or malignant.

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.

An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model.

Idiopathic pulmonary fibrosis is a chronic progressive disease of increasing prevalence for which there is no effective therapy. Increased oxidative stress associated with an oxidant-antioxidant imbalance is thought to contribute to disease progression. NADPH oxidases (Nox) are a primary source of reactive oxygen species within the lung and cardiovascular system.

Schwannomas of head and neck and review of literature.

Benign nerve cell tumours have been given various names like schwannoma, neurilemmoma, neurinoma, neurofibroma, spindle cell tumours etc. Extra cranial head and neck schwannomas usually present as solitary and well-demarcated lesions. The lesion can cause secondary symptoms, such as nasal obstruction, dysphasia, and hoarseness, depending upon the location of the lesion.

Role of Elicitors in Inducing Resistance in Plants against Pathogen Infection: A Review.

Disease control is largely based on the use of fungicides, bactericides, and insecticides-chemical compounds toxic to plant invaders, causative agents, or vectors of plant diseases. However, the hazardous effect of these chemicals or their degradation products on the environment and human health strongly necessitates the search for new, harmless means of disease control. There must be some natural phenomenon of induced resistance to protect plants from disease.

Isolated Sphenoid Pyocele with Thornwaldt's Cyst of Nasopharynx.

Isolated sphenoid sinusitis (ISS) is a rare entity. ISS accounts for about 1-2% of all sinus infections. Isolated sphenoid sinus involvement may include mucoceles, pyoceles and isolated mycotic infections.

Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of Drosophila melanogaster.

The simultaneous overexpression of multiple copies of Mn superoxide dismutase (SOD) and ectopic catalase (mtCat) transgenes in the mitochondria of the fruit fly, Drosophila melanogaster, was shown previously to diminish the life span. The hypothesis tested in this study was that this effect was due primarily to the presence of one or the other transgene. An alternative hypothesis was that both transgenes have additive, negative effects.

Mitochondrial peroxiredoxins are critical for the maintenance of redox state and the survival of adult Drosophila.

Drosophila mitochondria contain two peroxidases, peroxiredoxin 3 (dPrx3) and peroxiredoxin 5 (dPrx5), which together constitute the sole known intramitochondrial mechanism for the catalytic removal of hydrogen and organic peroxides. dPrx3 exists exclusively within mitochondria, whereas dPrx5 is also present in some other intracellular compartments. Levels of these two peroxiredoxins were genetically manipulated, singly and together, in D.

Prospective study of myringoplasty using different approaches.

Background: Myringoplasty is one of the various surgical techniques for the management of chronic supurative otitis media of tubotympanic type (CSOM-TT). The presence of a perforation of tympanic membrane with intermittent discharge and hearing loss of conductive nature are the indications of myringoplasty. Myringoplasty can be performed by any of the three approaches, i.

Benzodiazepine binding site occupancy by the novel GABAA receptor subtype-selective drug 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in rats, primates, and humans.

The GABA(A) receptor alpha2/alpha3 subtype-selective compound 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023; also known as MK-0777) is a triazolopyridazine that has similar, subnanomolar affinity for the benzodiazepine binding site of alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors and has partial agonist efficacy at the alpha2 and alpha3 but not the alpha1 or alpha5 subtypes. The purpose of the present study was to define the relationship between plasma TPA023 concentrations and benzodiazepine binding site occupancy across species measured using various methods. Thus, occupancy was measured using either in vivo [(3)H]flumazenil binding or [(11)C]flumazenil small-animal positron emission tomography (microPET) in rats, [(123)I]iomazenil gamma-scintigraphy in rhesus monkeys, and [(11)C]flumazenil PET in baboons and humans.

The plasma-occupancy relationship of the novel GABAA receptor benzodiazepine site ligand, alpha5IA, is similar in rats and primates.

Background And Purpose: alpha5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is a triazolophthalazine with subnanomolar affinity for alpha1-, alpha2-, alpha3- and alpha5-containing GABA(A) receptors. Here we have evaluated the relationship between plasma alpha5IA concentrations and benzodiazepine binding site occupancy in rodents and primates (rhesus monkey).

Experimental Approach: In awake rats, occupancy was measured at various times after oral dosing with alpha5IA (0.