A5060422552- HIV/AIDS drug development and treatment
- Hepatitis C virus research
- Chemical Synthesis and Analysis
- Neuroscience and Neuropharmacology Research
- Biochemical and Molecular Research
- Hepatitis B Virus Studies
- Asymmetric Synthesis and Catalysis
- Receptor Mechanisms and Signaling
- HIV Research and Treatment
- Coordination Chemistry and Organometallics
- Histone Deacetylase Inhibitors Research
- Liver Disease Diagnosis and Treatment
- Protein Degradation and Inhibitors
- PARP inhibition in cancer therapy
- Monoclonal and Polyclonal Antibodies Research
- DNA Repair Mechanisms
- Liver Disease and Transplantation
- Ion channel regulation and function
- Pharmacological Receptor Mechanisms and Effects
- Peptidase Inhibition and Analysis
- Synthesis and Biological Evaluation
- Phenothiazines and Benzothiazines Synthesis and Activities
- Quinazolinone synthesis and applications
- Pneumocystis jirovecii pneumonia detection and treatment
- Organ Transplantation Techniques and Outcomes
University of California, Davis
2023
University of Nebraska Medical Center
2023
University of Arizona
2017-2021
Banner - University Medical Center Phoenix
2016-2021
The University of Texas Southwestern Medical Center
2019-2020
University of Calgary
2019
University of Phoenix
2017
Institute of Molecular Biology and Pathology
2005-2015
Merck & Co., Inc., Rahway, NJ, USA (United States)
1997-2014
The University of Texas MD Anderson Cancer Center
2013
Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target chemotherapeutic intervention in treatment HIV-1 infection. We report here discovery Raltegravir, first HIV-integrase inhibitor approved by FDA HIV It derives from evolution 5,6-dihydroxypyrimidine-4-carboxamides N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition catalyzed strand transfer process. Structural...
We disclose the development of a novel series 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This was optimized to improve enzyme cellular activity, resulting PARP inhibitors display antiproliferation activities against BRCA-1 BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 1A2 identified metabolic concern, strategies pharmacokinetic properties are reported. These efforts...
ABSTRACT HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad coverage, a convenient dosing regimen important attributes future be used in combinations without interferon. In this communication, we report the preclinical profile...
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using molecular modeling-derived strategy. Building on the profile previous clinical compounds and exploring linker regions series allowed for optimization broad genotype mutant enzyme potency, cellular activity, rat liver exposure following oral dosing. These studies led identification candidate 15 (MK-5172), which is active against 1-3 clinically relevant enzymes has good plasma...
ABSTRACT The RNA-dependent RNA polymerase of hepatitis C virus (HCV) is the catalytic subunit viral amplification machinery and an appealing target for development new therapeutic agents against HCV infection. Nonnucleoside inhibitors based on a benzimidazole scaffold have been recently reported. Compounds this class are efficient replication in cell culture, thus providing attractive candidates further development. Here we report detailed analysis mechanism action selected inhibitors....
Poly(ADP-ribose) polymerases (PARPs) are involved in DNA repair following damage by endogenous or exogenous processes. It has become clear over the past decade that inhibition of PARP context defects other mechanisms provide a tumor specific way to kill cancer cells. We describe rationale for this approach and design discovery niraparib, potent PARP-1/2 inhibitor with good cell based activity, selectivity normal cells, oral bioavailability. Niraparib was characterized number preclinical...
The hepatitis C virus (HCV) polymerase is required for replication of the viral genome and a key target therapeutic intervention against HCV. We have determined crystal structures HCV complexed with two indole-based allosteric inhibitors at 2.3- 2.4-Å resolution. show that these bind to site on surface thumb domain. A cyclohexyl phenyl ring substituents, bridged by an indole moiety, fill closely spaced pockets, whereas carboxylate substituent forms salt bridge exposed arginine side chain....
It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole and reduced pKa piperazines compared to piperidines may be one possible explanation for these differences. To investigate this proposal we developed versatile synthetic strategies incorporation fluorine into ligands, producing novel 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, both piperazine...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT3'-(Arylmethyl)- and 3'-(Aryloxy)-3-phenyl-4-hydroxyquinolin- 2(1H)-ones: Orally Active Antagonists of the Glycine Site on NMDA ReceptorJanusz J. Kulagowski, Raymond Baker, Neil R. Curtis, Ian M. Mawer, Angela Moseley, Mark P. Ridgill, Michael Rowley, Stansfield, Paul D. Leeson, Cite this: Med. Chem. 1994, 37, 10, 1402–1405Publication Date (Print):May 1, 1994Publication History Published online1 May 2002Published inissue 1...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal synthesis of (+)-ophiobolin CMichael Rowley, Masamitsu Tsukamoto, and Yoshito KishiCite this: J. Am. Chem. Soc. 1989, 111, 7, 2735–2737Publication Date (Print):March 1, 1989Publication History Published online1 May 2002Published inissue 1 March 1989https://pubs.acs.org/doi/10.1021/ja00189a069https://doi.org/10.1021/ja00189a069research-articleACS PublicationsRequest reuse permissionsArticle Views2598Altmetric-Citations115LEARN ABOUT THESE...
A major issue in designing drugs as antagonists at the glycine site of NMDA receptor has been to achieve good vivo activity. series 4-hydroxyquinolone was found be active DBA/2 mouse anticonvulsant assay, but improvements vitro affinity were not mirrored by corresponding increases Here we show that binding compounds plasma protein limits their brain penetration. Relative protein, albumin, measured two different ways: a radioligand experiment or using an HPLC for wide structural range...
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXT5-(4-Chlorophenyl)-4-methyl-3-(1-(2- phenylethyl)piperidin-4-yl)isoxazole: A Potent, Selective Antagonist at Human Cloned Dopamine D4 ReceptorsMichael Rowley, Howard B. Broughton, Ian Collins, Raymond Baker, Frances Emms, Rosemarie Marwood, Shil Patel, Smita C. Ragan, Stephen Freedman, and Paul D. LeesonView Author Information Merck Sharp Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K. Cite this: J....
A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low selectivity alpha 2- and/or 3- over 1-containing GABA(A) subtypes and 5 subtypes. High appeared to be associated a coplanar conformation pyridone sulfur-containing 3-heteroaryl rings resulting from an attractive S.O intramolecular interaction. Functional (i.e., selective efficacy) 2 3...
The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation the optimal position for basic nitrogen in a series 2-phenyl-3-piperidylindoles, it was found that with at 3-position piperidine not necessary to further substitute order obtain good binding receptors. This meant compounds no longer had affinity IKr potassium channel, an issue previous 2-aryl-3-(4-piperidyl)indoles. Improvements could be made oral bioavailability...
The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. optimization of physicochemical properties, pharmacokinetic profiles, potency led to the identification 13 in series 18 N-methylpyrimidinone having low nanomolar activity cellular spread assay presence 50% normal human serum very good pharmacokinetics preclinical species.
Most full antagonists at the glycine site of NMDA receptor contain a carboxylic acid, which we believe to be detrimental penetration blood-brain barrier. By consideration pharmacophore, novel this have been designed in anionic functionality is vinylogous form 4-hydroxyquinolin-2(1H)-one. In series, 3-substituent necessary for binding, and correct manipulation group leads compounds such as 3-(3-hydroxyphenyl)propargyl ester 24 (L-701,273), with an IC50 displacement [3H]-L-689,560 binding 0.17...
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies in urgent demand. Compounds that block replication of subgenomic HCV RNA liver cells interest because their demonstrated antiviral effect the clinic. In followup to our recent report indole-N-acetamides (e.g., 1) potent allosteric inhibitors NS5B polymerase enzyme, we describe here optimization as cell-based inhibitors. The crystal structure 1 bound was guide design two-dimensional...
Allosteric inhibition of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase enzyme has recently emerged as a viable strategy toward blocking replication viral in cell-based systems. We report here novel class allosteric inhibitor that shows potent affinity for and effective subgenomic HCV HUH-7 cells. Inhibitors from this have promising characteristics further development anti-HCV agents.
Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target chemotherapeutic intervention in treatment AIDS that has also recently been confirmed clinical setting. We report here on design and synthesis N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as class agents which exhibits potent inhibition HIV-integrase-catalyzed strand transfer process. In current study, structural modifications these molecules...