A5090298784- Platelet Disorders and Treatments
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- HIV Research and Treatment
- Bioactive Compounds and Antitumor Agents
- Antiplatelet Therapy and Cardiovascular Diseases
- Heparin-Induced Thrombocytopenia and Thrombosis
- Synthesis and Biological Evaluation
- Chemical Reaction Mechanisms
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Cell Adhesion Molecules Research
- Microbial Natural Products and Biosynthesis
- Synthesis and Reactions of Organic Compounds
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Synthesis and Catalytic Reactions
- Cancer therapeutics and mechanisms
- Receptor Mechanisms and Signaling
- Synthetic Organic Chemistry Methods
- HER2/EGFR in Cancer Research
- Phosphodiesterase function and regulation
- Cholinesterase and Neurodegenerative Diseases
- Ferrocene Chemistry and Applications
- Neuropeptides and Animal Physiology
- Drug Transport and Resistance Mechanisms
United States Military Academy
2008-2020
Merck & Co., Inc., Rahway, NJ, USA (United States)
2008
Tufts University
2002
Yale University
1988-1990
Wesleyan University
1988
The process of integrating the reverse-transcribed HIV-1 DNA into host chromosomal is catalyzed by virally encoded enzyme integrase (IN). Integration requires two metal-dependent reactions, 3' end processing and strand transfer. Compounds that contain a diketo acid moiety have been shown to selectively inhibit transfer reaction IN in vitro infected cells are effective as inhibitors replication. To characterize molecular basis inhibition, we used functional assays binding evaluate series...
The increasing incidence of resistance to current HIV-1 therapy underscores the need develop antiretroviral agents with new mechanisms action. Integrase, one three viral enzymes essential for replication, presents an important yet unexploited opportunity drug development. We describe here identification and characterization L-870,810, a small-molecule inhibitor integrase potent antiviral activity in cell culture good pharmacokinetic properties. L-870,810 is...
Diketo acids such as L-731,988 are potent inhibitors of HIV-1 integrase that inhibit integration and viral replication in cells. These compounds exhibit the unique ability to strand transfer activity absence an effect on 3′ end processing. To understand reasons for this distinct inhibitory profile, we developed a scintillation proximity assay permits analysis radiolabeled inhibitor binding function. High-affinity is shown require assembly specific complex long terminal repeat. The...
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...
Naphthyridine 7 inhibits the strand transfer of integration process catalyzed by integrase with an IC50 10 nM and 95% spread HIV-1 infection in cell culture at 0.39 microM. It does not exhibit cytotoxicity < or =12.5 microM shows a good pharmacokinetic profile when dosed orally to rats. The antiviral activity its effect on were confirmed using viruses specific mutations.
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...
ADVERTISEMENT RETURN TO ISSUELetterNEXT4-Aryl-2,4-dioxobutanoic Acid Inhibitors of HIV-1 Integrase and Viral Replication in CellsJohn S. Wai, Melissa Egbertson, Linda Payne, Thorsten E. Fisher, Mark W. Embrey, Lekhanh O. Tran, Jeffrey Y. Melamed, H. Marie Langford, James P. Guare,, Linghang Zhuang, Vanessa Grey, Joseph Vacca, M. Katharine Holloway, Adel Naylor-Olsen, Daria J. Hazuda, Peter Felock, Abigail L. Wolfe, Kara A. Stillmock, William Schleif, Lori Gabryelski, Steven D. YoungView...
We have identified several series of small molecule inhibitors TrkA with unique binding modes. The starting leads were chosen to maximize the structural and mode diversity derived from a high throughput screen our internal compound collection. These optimized for potency selectivity employing structure based drug design approach adhering principles ligand efficiency affinity without overly relying on lipophilic interactions. This endeavor resulted in identification pan-Trk inhibitor that...
The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development CNS directed therapeutics. We others have investigated muscarinic acetylcholine 4 (M4) positive allosteric modulators (PAMs) for the treatment symptoms associated with neuropsychiatric disorders. In this article, we describe synthesis, vitro, vivo characterization a series central pyridine-related M4 PAMs that can be conveniently radiolabeled...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe characterization of intermediates in the mitomycin activation cascade: a practical synthesis an aziridinomitoseneSamuel J. Danishefsky and Melissa. EgbertsonCite this: Am. Chem. Soc. 1986, 108, 15, 4648–4650Publication Date (Print):July 1, 1986Publication History Published online1 May 2002Published inissue 1 July 1986https://pubs.acs.org/doi/10.1021/ja00275a065https://doi.org/10.1021/ja00275a065research-articleACS PublicationsRequest reuse...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEfficient preparation of intermediates corresponding to C22-C27 and C28-C34 FK-506Robert G. Linde II, Melissa Egbertson, Robert S. Coleman, A. Brian Jones, Samuel J. DanishefskyCite this: Org. Chem. 1990, 55, 9, 2771–2776Publication Date (Print):April 1, 1990Publication History Published online1 May 2002Published inissue 1 April 1990https://pubs.acs.org/doi/10.1021/jo00296a040https://doi.org/10.1021/jo00296a040research-articleACS...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTModeling of the electrophilic activation mitomycins: chemical evidence for intermediacy a mitosene semiquinone as active electrophileMelissa Egbertson and Samuel J. DanishefskyCite this: Am. Chem. Soc. 1987, 109, 7, 2204–2205Publication Date (Print):April 1, 1987Publication History Published online1 May 2002Published inissue 1 April 1987https://pubs.acs.org/doi/10.1021/ja00241a061https://doi.org/10.1021/ja00241a061research-articleACS...
The synthesis and pharmacology of 4, a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggregation human gel-filtered platelets with an IC50 8 nM demonstrated 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing isoindolinone backbone. Flow cytometry studies revealed that binding to resting is diffusion-controlled process (kon = 3.3 x 10(6) M-1 s-1) binds dog comparable (Kd 0.04 0.07 nM,...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA synthetic route to the tricarbonyl region of FK-506Melissa Egbertson and Samuel J. DanishefskyCite this: Org. Chem. 1989, 54, 1, 11–12Publication Date (Print):January 1989Publication History Published online1 May 2002Published inissue 1 January 1989https://pubs.acs.org/doi/10.1021/jo00262a005https://doi.org/10.1021/jo00262a005research-articleACS PublicationsRequest reuse permissionsArticle Views305Altmetric-Citations34LEARN ABOUT THESE...
Abstract Herein we describe the discovery and optimization of a new series 2,3‐disubstituted 2,3,6‐trisubstituted muscarinic acetylcholine receptor 4 (M ) positive allosteric modulators (PAMs). Iterative libraries enabled rapid exploration one‐dimensional structure–activity relationships (SAR) identification potency‐enhancing heterocycle N ‐alkyl pyrazole substituents. Further led to potent, receptor‐subtype‐selective, brain‐penetrant tool compound 24...
A critical function of fibrinogen in hemostasis and thrombosis is to mediate platelet aggregation by binding selectively an activated form glycoprotein (GP) IIb/IIIa. Although numerous peptide nonpeptide receptor antagonists have been described, their selectivity for resting platelets has not explored. Therefore, dissociation constants GP IIb/IIIa two biochemically separated forms purified were determined competitive displacement the dansyl fluorophore containing antagonist L-736,622. Also,...
Antagonists of platelet glycoprotein IIb/IIIa (GPIIb/IIIa) represent a new therapeutic approach in inhibiting aggregation, thus providing powerful form antithrombotic therapy. The measurement binding arginine-glycine-aspartic acid (RGD) peptidomimetics to GPIIb/IIIa on platelets is key for the further understanding ligand-receptor interactions and, thus, design antagonists. flow cytometric dynamic and equilibrium parameters two potent RGD peptidomimetics, L-762,745 L-769,434, containing...