A5006147441- Epigenetics and DNA Methylation
- Uterine Myomas and Treatments
- Receptor Mechanisms and Signaling
- Synthesis and Biological Evaluation
- Neuroscience and Neuropharmacology Research
- Fluorine in Organic Chemistry
- Computational Drug Discovery Methods
- Organic Chemistry Cycloaddition Reactions
- Neurotransmitter Receptor Influence on Behavior
- Chemical Synthesis and Analysis
- Synthesis and Catalytic Reactions
- Histone Deacetylase Inhibitors Research
- Tryptophan and brain disorders
- Synthesis and Reactions of Organic Compounds
- Pharmacological Receptor Mechanisms and Effects
- Genetics and Neurodevelopmental Disorders
- Protein Degradation and Inhibitors
- Alzheimer's disease research and treatments
- Click Chemistry and Applications
- Cholinesterase and Neurodegenerative Diseases
- Synthesis of β-Lactam Compounds
- Cancer-related Molecular Pathways
- Neuropeptides and Animal Physiology
- Polyomavirus and related diseases
- Amino Acid Enzymes and Metabolism
Temple University
2016-2025
Indiana University – Purdue University Indianapolis
2022
Indiana University School of Medicine
2022
University of Toledo
2022
Temple College
2021
University of Florida
2021
Johns Hopkins University
2021
University of Rochester
2021
Center for Discovery
2016
Creative Commons
2014
The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is novel salt form the isolated major active metabolite venlafaxine. Competitive radioligand binding assays were performed using cells expressing either human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) (hNET) with <i>K</i><sub>i</sub> values for 40.2 ± 1.6 and 558.4 121.6 nM, respectively. showed weak affinity (62% inhibition at 100 μM) dopamine (DA) transporter....
Small-molecule BET bromodomain inhibitors (BETis) are actively being pursued in clinical trials for the treatment of a variety cancers, but mechanisms resistance to BETis remain poorly understood. Using mass spectrometry approach that globally measures kinase signaling at proteomic level, we evaluated response kinome targeted BETi panel BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects BETi, OC cells acquired following sustained with JQ1. Through...
The presenilin containing γ-secretase complex is responsible for the regulated intramembraneous proteolysis of amyloid precursor protein (APP), Notch receptor, and a multitude other substrates. γ-Secretase catalyzes final step in generation Aβ<sub>40</sub> Aβ<sub>42</sub> peptides from APP. Amyloid β-peptides (Aβ peptides) aggregate to form neurotoxic oligomers, senile plaques, congophilic angiopathy, some cardinal pathologies associated with Alzheimer9s disease. Although inhibition this...
Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse silencing of tumor suppressor genes (TSG). In screen drugs reactivate silenced gene expression in colon cells, found three classical targeted (DNA methylation and histone deacetylase inhibitors) 11 other induced methylated CpG island promoters driving reporter (GFP) as well endogenous TSGs multiple cell lines. These newly identified...
ABSTRACT Cryptococcosis is an infectious disease of global significance for which new therapies are needed. Repurposing previously developed drugs indications can expedite the translation from bench to beside. Here, we characterized anti-cryptococcal activity and antifungal mechanism estrogen receptor antagonists related breast cancer tamoxifen toremifene. Tamoxifen toremifene fungicidal synergize with fluconazole amphotericin B in vitro . In a mouse model disseminated cryptococcosis, at...
Indole oxoacetic acid derivatives were prepared and evaluated for in vitro binding to inactivation of human plasminogen activator inhibitor-1 (PAI-1). SAR based on biochemical, physiological, pharmacokinetic attributes led identification tiplaxtinin as the optimal selective PAI-1 inhibitor. Tiplaxtinin exhibited vivo oral efficacy two different models acute arterial thrombosis. The remarkable preclinical safety metabolic stability profiles advancing compound clinical trials.
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTDesign, Synthesis, and Preclinical Characterization of Novel, Highly Selective Indole EstrogensChris P. Miller, Michael D. Collini, Bach Tran, Heather A. Harris, Yogendra Kharode, James T. Marzolf, Robert Moran, Ruth Henderson, Reinhold H. W. Bender, Rayomond J. Unwalla, Lee M. Greenberger, John Yardley, Magid Abou-Gharbia, C. Richard Lyttle, Barry S. KommView Author Information Wyeth-Ayerst Research, Chemical Sciences, 145 King Prussia Road,...
The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis Alzheimer's disease. Accordingly, key determinant disease onset and progression is appropriate balance between Abeta production clearance. Enzymes responsible for degradation are not well understood, and, thus far, it has been possible enhance catabolism by pharmacological manipulation. We provide evidence increased after inhibition plasminogen activator inhibitor-1 (PAI-1)...
Recent data has suggested that the 5-hydroxytryptamine (5-HT)<sub>1A</sub> receptor is involved in cognitive processing. A novel 5-HT<sub>1A</sub> antagonist, 4-cyano-<i>N</i>-{2<i>R</i>-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-<i>N</i>-pyridin-2-yl-benzamide HCl (lecozotan), which been characterized multiple vitro and vivo pharmacological assays as a drug to treat dysfunction, reported. In binding intrinsic activity determinations demonstrated lecozotan potent...
Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target (mTOR) binding region yields ligands, WYE-592 and ILS-920, with potent activities in cortical neuronal cultures, efficacy a rodent model for ischemic stroke, significantly reduced Surprisingly, both compounds showed higher selectivity FKBP52 versus FKBP12, contrast to previously ligands. Affinity purification revealed two key proteins,...
SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting metabolically labile methyl groups 9 trifluoromethyl afforded more stable analogue 10, had improved vivo potency. Further side chain modification potent begacestat (5), was selected for development treatment of Alzheimer's disease.
Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% reproductive-age women. Despite being primary cause hysterectomy in United States, accounting for 200,000 procedures annually, etiology leiomyoma remains largely unknown. As a basis understanding pathogenesis and identifying targets pharmacotherapy, we conducted transcriptional profiling unaffected from humans Eker rats, best characterized preclinical model leiomyomata. A global...
Spiroaziridines, carboxanilides and spirosuccinimides were prepared as part of a study concerned with the relationships between chemical structure biological activity.Several recently reported ~p i r o f l ~o e n s ~' ~ have been found to exhibit antileukemic activity in
Currently the entire human population is in midst of a global pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2). This highly pathogenic virus has to date >71 million infections and >1.6 deaths >180 countries. Several vaccines drugs are being studied as possible treatments or prophylactics this viral infection. M3CLpro (coronavirus main cysteine protease) promising drug target it significant role replication. Here we use X-ray crystal structure complex with...
Long-term treatment of female C3H-Avy/A (obese) and C3H-A/A (non-obese) mice with dehydroepiandrosterone, an adrenal steroid found in subnormal levels women predisposed to develop breast cancer, reduces weight gain without suppressing appetite significantly inhibits the development spontaneous cancer. This also antagonizes capacity tumor promoter, 12-0-tetradecanoyl-phorbol-13-acetate, stimulate 3H-thymidine incorporation mouse epidermis a cultured rat kidney epithelial cell line.
The pharmaceutical industry is facing enormous challenges, including reduced efficiency, stagnant success rate, patent expirations for key drugs, fierce price competition from generics, high regulatory hurdles, and the industry's perceived tarnished image. Pharma has responded by embarking on a range of initiatives. Other sectors, NIH, have also responded. Academic drug discovery groups appeared to support transition innovative academic discoveries ideas into attractive opportunities. Part 1...
Prior to genetic mapping, the majority of drug discovery efforts involved phenotypic screening, wherein compounds were screened in either vitro or vivo models thought mimic disease state interest. While never completely abandoning approaches, labor intensive nature such tests encouraged pharmaceutical industry move away from them favor target-based discovery, which facilitated throughput and allowed for efficient screening large numbers compounds. However, a consequence reliance on was an...
Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared examined in various receptor binding behavioral tests to determine their serotonin activities. Many compounds demonstrated modest high affinity for 5-HT1A receptors, with 9, 13, 23, 33, 34, 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, relatively receptors (Ki = 8 nM) acceptable selectivity versus D2 708 mM); however, it lacked...
The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 CGS-19755 (5) in [3H]CPP binding assay, stimulated [3H]TCP NMDA-induced lethality model mice. A single bolus dose of compound administered intravenously following permanent occlusion middle...
Journal Article Inhibition of DNA synthesis in mouse epidermis and breast epithelium by dehydroepiandrosterone related steroids Get access Laura L. Pashko, Pashko Fels Research Institute Department Chemistry, Temple UniversityPhiladelphia, PA 19140, USA. Search for other works this author on: Oxford Academic PubMed Google Scholar Arthur G. Schwartz, Schwartz Magid Abou-Gharbia, Abou-Gharbia Daniel Swern Carcinogenesis, Volume 2, Issue 8, 1981, Pages 717–721,...