A5031350782- Synthesis and Biological Evaluation
- Platelet Disorders and Treatments
- Cell Adhesion Molecules Research
- Neuroscience and Neuropharmacology Research
- Protein Kinase Regulation and GTPase Signaling
- Receptor Mechanisms and Signaling
- HER2/EGFR in Cancer Research
- Chemical Synthesis and Analysis
- Cancer-related Molecular Pathways
- Ion channel regulation and function
- Synthesis of heterocyclic compounds
- Quinazolinone synthesis and applications
- Microtubule and mitosis dynamics
- Hepatitis B Virus Studies
- Antiplatelet Therapy and Cardiovascular Diseases
- Hepatitis C virus research
- Sleep and Wakefulness Research
- PI3K/AKT/mTOR signaling in cancer
- Synthesis and Reactions of Organic Compounds
- Pharmacological Receptor Mechanisms and Effects
- Monoclonal and Polyclonal Antibodies Research
- Sulfur-Based Synthesis Techniques
- Phenothiazines and Benzothiazines Synthesis and Activities
- Heparin-Induced Thrombocytopenia and Thrombosis
- Chemical Reaction Mechanisms
Janssen (United States)
2017-2022
Merck & Co., Inc., Rahway, NJ, USA (United States)
1990-2018
Acorda Therapeutics (United States)
2015
United States Military Academy
2005-2014
Merck (Japan)
2008
Duke University Hospital
2002
Duke Medical Center
2002
University of Pennsylvania
1996
University of Cincinnati
1983
University of California, San Diego
1975
Despite increased understanding of the biological basis for sleep control in brain, few novel mechanisms treatment insomnia have been identified recent years. One notable exception is inhibition excitatory neuropeptides orexins A and B by design orexin receptor antagonists. Herein, we describe how efforts to understand origin poor oral pharmacokinetics a leading HTS-derived diazepane antagonist led identification compound 10 with 7-methyl substitution on core. Though displayed good potency,...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNon-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitorsGeorge D. Hartman, Melissa S. Egbertson, Wasyl Halczenko, William L. Laswell, Mark E. Duggan, Robert Smith, Adel M. Naylor, Patricia Manno, J. Lynch, Cite this: Med. Chem. 1992, 35, 24, 4640–4642Publication Date (Print):November 1, 1992Publication History Published online1 May 2002Published inissue 1 November...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNon-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as Mimic for Arg-Gly-AspMelissa S. Egbertson, Charles T.-C. Chang, Mark E. Duggan, Robert J. Gould, Wasyl Halczenko, George D. Hartman, William L. Laswell, Joseph Lynch Jr., Lynch, and Cite this: Med. Chem. 1994, 37, 16, 2537–2551Publication Date (Print):August 5, 1994Publication History Published online1 May 2002Published inissue 5 August...
Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment cancer with the potential to overcome limitations associated currently employed cytotoxic agents. Herein, we describe C2-hydroxymethyl dihydropyrrole KSP inhibitor (11) that circumvents hERG channel binding and poor in vivo potency, issues limited earlier compounds from our program. However, introduction group caused 11 be substrate cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered previous...
The hepatitis B virus (HBV) core protein is essential for HBV replication and an important target antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of compound bound protein. NVR-010-001-E2 can induce assembly wild-type Y132A mutant proteins thermostabilize with a Tm increase more than 10 °C. binds at dimer-dimer interface proteins, forms new interaction surface promoting protein-protein interaction, induces assembly, increases stability....
NVR 3-778 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that can inhibit HBV replication. We performed proof-of-concept study to examine the safety, pharmacokinetics, and antiviral activity of in patients with chronic infection.We phase 1 73 envelope antigen (HBeAg)-positive infection without cirrhosis. In 2-part (part New Zealand part 2 Hong Kong, Singapore, Taiwan, Korea, United States), were randomly assigned groups given oral (100 mg, 200 or 400 mg daily 600 1000...
Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many these agents fail to meet patient needs respect sleep onset, maintenance, next-day residual effects have issues related tolerance, memory disturbances, balance. Orexin neuropeptides are regulators wakefulness, orexin antagonism has been identified as novel mechanism for...
The hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle, and antiviral agents that target are being developed. Capsid assembly modulators (CAMs) compounds misdirect capsid assembly, resulting suppression of HBV replication virion production. Besides DNA, circulating RNA has been detected patient serum can be associated with treatment response. Here we studied effect CAMs on production extracellular using infected HepaRG cells primary human...
This report describes the discovery of first centrally active allosteric modulators metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class potent positive mGluR5 that potentiate response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof...
The novel T-type antagonist ( S)- 5 has been prepared and evaluated in vitro vivo assays for calcium ion channel activity. Structural modification of the piperidine leads 1 2 afforded fluorinated 5, a potent selective that displayed CNS efficacy without adverse cardiovascular effects.
NVR 3-778 is the first capsid assembly modulator (CAM) that has demonstrated antiviral activity in hepatitis B virus (HBV)-infected patients. inhibited generation of infectious HBV DNA-containing particles with a mean 50% effective concentration (EC50) 0.40 µM HepG2.2.15 cells. The profile indicates pan-genotypic and lack cross-resistance nucleos(t)ide inhibitors replication. combination analogs vitro resulted additive or synergistic activity. Mutations within hydrophobic pocket at...
A series of 5-substituted thieno[2,3-b]- and thieno[3,2-b)- thieno[3,2-b)thiophene-2-sulfonamides was prepared evaluated for topical ocular hypotensive activity in glaucoma models. The 5-substituents were varied to maximize both inhibitory potency against carbonic anhydrase water solubility. At the same time, these substituents order obtain compounds with appropriate pKa minimize pigment binding iris. All variables optimized best compound, 5-[[(methoxyethyl)[(methoxyethyl)ethyl]...
Novel 3-cyanoisoquinoline Kv1.5 antagonists have been prepared and evaluated in vitro vivo assays for inhibition of the potassium channel its associated cardiac current, IKur. Structural modifications isoquinolinone lead 1 afforded compounds with excellent potency, selectivity, oral bioavailability.
The discovery of a novel series potent and selective T-type calcium channel antagonists is reported. Initial optimization high-throughput screening leads afforded 1,4-substituted piperidine amide 6 with good potency limited selectivity over hERG L-type channels other off-target activities. Further SAR on reducing the basicity introducing polarity led to 3-axial fluoropiperidine 30 significantly improved profile. Compound showed oral bioavailability brain penetration across species. In rat...
Abstract Silent Night : Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for treatment insomnia. Herein, we describe discovery dual (OX 1 R/OX 2 R) receptor antagonist featuring 1,4‐diazepane central constraint that blocks signaling in vivo. In telemetry‐implanted rats, oral administration this produced decrease wakefulness, while increasing REM and non‐REM sleep. magnified image