A5030735043- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Parkinson's Disease Mechanisms and Treatments
- Neuroscience and Neuropharmacology Research
- Lung Cancer Treatments and Mutations
- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Alzheimer's disease research and treatments
- Carcinogens and Genotoxicity Assessment
- Health Systems, Economic Evaluations, Quality of Life
- Drug-Induced Adverse Reactions
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- DNA Repair Mechanisms
- Antifungal resistance and susceptibility
- Liver Disease Diagnosis and Treatment
- Pharmacological Effects and Toxicity Studies
- Fungal Infections and Studies
- Drug-Induced Hepatotoxicity and Protection
- Reproductive System and Pregnancy
- Economic and Financial Impacts of Cancer
- Bioinformatics and Genomic Networks
- Asthma and respiratory diseases
- Cancer Cells and Metastasis
- Barrier Structure and Function Studies
- Phosphodiesterase function and regulation
Pfizer (United States)
2013-2024
Université de Montréal
2010
Experimental Pathology Laboratories
2006-2007
Triangle
2006-2007
University of Tennessee at Knoxville
2006
North Carolina State University
2005-2006
National Institute of Environmental Health Sciences
2002-2005
Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise increased activity. As such, inhibitors are potentially useful treatment of PD. We herein disclose discovery and optimization a novel series potent inhibitors, focusing on improving kinome selectivity using surrogate crystallography approach. This resulted...
Bile acids (BAs) have been studied as potential biomarkers of drug-induced liver injury. However, the relationship between levels individual BAs and specific forms injury remains to be fully understood. Thus, we set out evaluate cholic acid (CA), glycocholic (GCA), taurocholic (TCA) in rodent toxicity studies. We developed a sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay applicable rat mouse serum evaluated comparison with classical hepatotoxicity (alanine...
Morphological changes in the lungs of macaques induced by several different LRRK2 inhibitors are reversible and do not lead to lung deficits.
To respond to potential adverse exposures properly, health care providers need accurate indicators of exposure levels. The are particularly important in the case acetaminophen (APAP) intoxication, leading cause liver failure U.S. We hypothesized that gene expression patterns derived from blood cells would provide useful acute test this hypothesis, we used a data set rats exposed APAP train classifiers two prediction algorithms and extract for using profiling algorithm. Prediction accuracy...
Inhibition of β-secretase BACE1 is considered one the most promising approaches for treating Alzheimer's disease. Several structurally distinct inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but target mediating this has not identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as principal off-target human cells. We find that several blocked CatD activity cells with much greater potency than displayed...
We hypothesized that the mouse liver tumor response to non-genotoxic carcinogens would involve some common early gene and protein expression changes could ultimately be used predict chemical hepatocarcinogenesis. In order identify a panel of genes test, we analyzed global differences in livers from B6C3F1 mice following dietary treatment with two rodent carcinogens, benzodiazepine anti-anxiety drug oxazepam (2500 p.p.m.) hypolipidemic agent Wyeth (Wy)-14,643 (500 compared untreated mice....
A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for treatment Alzheimer's disease is alignment potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) BACE2. The potential liabilities inhibiting BACE2 chronically have only recently begun to emerge impacts processing premelanosome (PMEL17) disrupts melanosome morphology resulting a depigmentation phenotype. Herein, we describe...
Many factors that can modulate the risk of developing uterine leiomyoma have been identified, including parity. Epidemiological data on decreased this disease has subject to different interpretations regarding whether pregnancy per se is protective or, as leiomyomas are a major cause infertility, women develop these tumors less fertile and thus lower rates. We utilized an animal model genetically predisposed investigate potential effect disease. Female Eker rats carry mutation in tuberous...
Abstract Background Cancer cachexia is a complex metabolic disease with unmet medical need. Although many rodent models are available, none identical to the human disease. Therefore, development of new preclinical that simulate some physiological, biochemical, and clinical characteristics valuable. The HT‐1080 fibrosarcoma tumour cell line was reported induce in mice. purpose this work determine how well model could recapitulate examine its technical performance. Furthermore, efficacy...
Gene expression profiling, metabolomic screens, and other high-dimensional methods have become an integral part of many biological investigations. To facilitate interpretation these data, it is important to detailed phenotypic data—including histopathology—to which data can be associated, or anchored. However, as the amount increases, associations within across difficult visualize interpret. We developed approach for categorizing clustering biologically related histopathological diagnoses...
Abstract Putative gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2), resulting increased activity and cellular toxicity, are a leading genetic cause of Parkinson’s disease (PD). Hence, there is strong interest developing LRRK2 inhibitors as disease-modifying therapy. Published reports that dosing with two (GNE-7915 GNE-0877) induce histopathological changes the lung non-human primates Fuji et al. 2015 ( 1 ) raised concerns about potential safety liability inhibitors. In...
Benzene and ethylene oxide are multisite carcinogens in rodents classified as human by the National Toxicology Program. In 2-year mouse studies, both chemicals induced mammary carcinomas. We examined spontaneous, benzene-, oxide-induced carcinomas for p53 protein expression, using immunohistochemistry, (exons 5–8) H -ras (codon 61) mutations cycle sequencing techniques. expression was detected 42% (8/19) of 43% (6/14) 67% (8/12) However, semiquantitative evaluation revealed that benzene-...
Ethylene oxide is a multisite carcinogen in rodents and classified as human by the National Toxicology Program. In 2-year mouse studies, ethylene (EO) induced lung, Harderian gland (HG), uterine neoplasms. We evaluated representative EO-induced equivalent spontaneous neoplasms for K- ras mutations codons 12, 13, 61. were identified 100% (23/23) of lung 25% (27/108) Codon 12 G to T transversions common (21/23) but infrequent (1/108). K -ras found 86% (18/21) HG 7% (2/27) 13 C codon...
The objective of this study was to determine the shortest period time necessary detect histologic evidence estrous cycle disruption in Sprague-Dawley rats treated for up 28 days with aromatase inhibitor exemestane at 1,000 mg/kg. Rats were evaluated on day 5, 8, 15, or 29. Vaginal mucification, uterine and cervical epithelial atrophy, luminal vacuolation, decreased granulocytes, hypertrophy/hyperplasia mammary ducts alveoli noted by 5 persisted throughout study. From 8 29, absence recent...
Three orally administered metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators caused skin lesions consistent with delayed type-IV hypersensitivity in cynomolgus macaques 2- and 12-week toxicity studies. Several monkeys developed macroscopic multiple locations after 8 to 9 days of dosing; the most prominent effects involved genital region males generalized erythema occurred both sexes. Microscopic clinically affected unaffected areas were characterized by lymphocytic...
The female reproductive cycle is orchestrated by cyclical and coordinated hormonal changes under the direction of hypothalamic-pituitary-gonadal (HPG) axis. Any disruption HPG axis may lead to functional structural alterations in system. Test article-related disturbances estrous can be recognized nonclinical toxicity studies staging based on microscopic evaluation organs. In chronic rat studies, an additional complication development senescence, which associated with natural leading system...
Mutations in both p53 and BRCA2 are commonly seen together human tumors suggesting that the loss of genes enhances tumor development. To elucidate this interaction an animal model, mice lacking carboxy terminal domain Brca2 were crossed with heterozygous mice. Females from intercross then irradiated acute dose 5 Gy ionizing radiation at weeks age compared to nonirradiated controls. We found decreased survival timing onsets, significantly higher overall incidences prevalence particular...
Background:Blastomycosis is a common systemic fungal infection in dogs. Hypothesis:Dogs with cardiovascular involvement may have abnormalities electrical conduction and valvular function, worse prognosis. Animals:Eight client‐owned animals. Methods:Dogs lesions caused by blastomycosis were identified from retrospective evaluation of medical records. Results:Five dogs had de novo infections 3 recurrences previously treated infections. Harsh labored breathing, lethargy, anorexia the most...
The requirements for safe testing of pharmaceuticals in humans places substantial emphasis on the translation safety performed animals to man.
Drug-induced vascular injury in nonclinical toxicity studies has been a difficult problem for the pharmaceutical industry decades. Drugs associated with include several classes of antibacterial agents, antimalarials, antivirals, antiinflammatory and molecules manipulating multiple mechanisms neurologic diseases, cardiovascular diabetes mellitus. While some action (e.g., dopamine receptor agonists or antagonists, phosphodiesterase inhibitors, adrenergic endothelin compounds that modulate...
Blastomycosis is a common systemic fungal infection in dogs.Dogs with cardiovascular involvement may have abnormalities electrical conduction and valvular function, worse prognosis.Eight client-owned animals.Dogs lesions caused by blastomycosis were identified from retrospective evaluation of medical records.Five dogs had de novo infections 3 recurrences previously treated infections. Harsh labored breathing, lethargy, anorexia the most historic complaints. Three syncope. Physical...
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated distinct series of NAMs. Increasing sp3 character high-throughput screening hit 40 afforded novel morpholinopyrimidone NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable...