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Your search keyword '"Matthew M. Zrada"' showing total 5 results
Start Over Author "Matthew M. Zrada" Topic biochemistry
5 results on '"Matthew M. Zrada"'

1. MK-8825: A potent and selective CGRP receptor antagonist with good oral activity in rats

Author

Samuel L. Graham, Christine Fandozzi, Eric L. Moore, Donnette D. Staas, Ian M. Bell, Nova Sain, Joseph G. Bruno, Steven N. Gallicchio, Harold G. Selnick, Christopher A. Salvatore, Mark O. Urban, Rebecca B. White, Matthew M. Zrada, Amy Calamari, C. Blair Zartman, Amanda L. Kemmerer, Joseph P. Vacca, Stefanie A. Kane, Craig A. Stump, and Scott D. Mosser

Subjects
medicine.medical_specialty, Pyridines, Migraine Disorders, Clinical Biochemistry, Administration, Oral, Biological Availability, Pharmaceutical Science, Calcitonin gene-related peptide, Pharmacology, Biochemistry, Mice, chemistry.chemical_compound, Dogs, Species Specificity, Calcitonin Gene-Related Peptide Receptor Antagonists, In vivo, Internal medicine, Drug Discovery, medicine, Animals, Humans, Potency, Spiro Compounds, Receptor, Molecular Biology, Analgesics, Chemistry, Organic Chemistry, Antagonist, Macaca mulatta, Rats, Blockade, Disease Models, Animal, Endocrinology, Pharmacodynamics, Molecular Medicine, Acetamide, Receptors, Calcitonin Gene-Related Peptide
Abstract

Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.

Published
2012
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2. Development of an efficient and selective radioligand for bradykinin B1 receptor occupancy studies

Author

J. Fred Hess, Michael A. Wallace, Rick W. Ransom, Douglas J. Pettibone, C. Meacham Harrell, Kathy L. Murphy, Matthew M. Zrada, Roger M. Freidinger, M. Kristine Markowitz, Bang-Lin Wan, Dai-Shi Su, Mark G. Bock, Dennis C. Dean, R. S. L. Chang, S. S. O'malley, and Conrad E. Raab

Subjects
Clinical Biochemistry, Pharmaceutical Science, Bradykinin, Pharmacology, Ligands, Receptor, Bradykinin B1, Sulfur Radioisotopes, Binding, Competitive, digestive system, Biochemistry, Animals, Genetically Modified, Radioligand Assay, Structure-Activity Relationship, chemistry.chemical_compound, Quinoxalines, Drug Discovery, Radioligand, Animals, Humans, Receptor, Molecular Biology, Organic Chemistry, Antagonist, Ligand (biochemistry), In vitro, Rats, Bradykinin B1 Receptor Antagonists, chemistry, Isotope Labeling, Molecular Medicine, Transgenic Rats, Ex vivo
Abstract

We have developed an efficient and selective radioligand, the [35S]-radiolabeled dihydroquinoxalinone derivative, 4, for an ex vivo receptor occupancy assay in transgenic rats over-expressing the human bradykinin B1 receptor.

Published
2004
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3. 8-Hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors

Author

Lori J. Gabryelski, Daria J. Hazuda, Thorsten E. Fisher, M. Reza Anari, Terry A. Lyle, Joseph P. Vacca, John S. Wai, Steven D. Young, Boyoung Kim, Matthew M. Zrada, William A. Schleif, Donnette D. Staas, Christopher J. Kochansky, and Peter J. Felock

Subjects
Stereochemistry, T-Lymphocytes, Clinical Biochemistry, Pharmaceutical Science, Integrase inhibitor, HIV Integrase, Biochemistry, Cell Line, Tumor, Drug Discovery, Humans, HIV Integrase Inhibitors, Molecular Biology, chemistry.chemical_classification, biology, Chemistry, Organic Chemistry, Biological activity, biology.organism_classification, Nucleotidyltransferase, Integrase, Enzyme, Viral replication, Enzyme inhibitor, Pyrazines, Lentivirus, biology.protein, Molecular Medicine
Abstract

A series of potent novel 8-hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 12 is active against replication of HIV-1 in cell culture with a CIC(95) of 0.31microM. Further SAR exploration led to the preparation of pseudosymmetrical tricyclic pyrrolopyrazine inhibitors 23 and 24 with further improvement in antiviral activity.

Published
2007

4. Kinesin spindle protein (KSP) inhibitors. Part V: discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by beta-fluorination to overcome cellular efflux by P-glycoprotein

Author

David B. Whitman, Nancy E. Kohl, Hans E. Huber, Eileen S. Walsh, Robert M. Garbaccio, George D. Hartman, Kelly Hamilton, Carolyn A. Buser, Weikang Tao, Matthew M. Zrada, Michael J. Breslin, Robert B. Lobell, Marc Abrams, Paul J. Coleman, Christopher D. Cox, Mark E. Fraley, and Vicki J. South

Subjects
Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Kinesins, Biochemistry, Drug Discovery, Side chain, Pyrroles, ATP Binding Cassette Transporter, Subfamily B, Member 1, Beta (finance), Molecular Biology, Cytoskeleton, P-glycoprotein, biology, Propylamines, Chemistry, Organic Chemistry, Water, Biological Transport, Fluorine, Hydrogen-Ion Concentration, Solubility, Cell culture, Cancer cell, biology.protein, Molecular Medicine, Kinesin, Amine gas treating, Efflux
Abstract

Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs.

Published
2007

5. A potent and orally active HIV-1 integrase inhibitor

Author

Yvonne M. Leonard, Gregory Moyer, Wei Han, Jeffrey Y. Melamed, Nancy N. Tsou, Lixia Jin, H. Marie Moritz, Amanda R. Cortes, D. S. Perlow, William A. Schleif, Lori J. Gabryelski, Michelle S. Kuo, Marc V. Witmer, Melissa S. Egbertson, Matthew P. Braun, Wei Xu, Peter J. Felock, Steven D. Young, Matthew M. Zrada, Michael D. Miller, Mark Embrey, Kellem Kassahun, Audrey A. Wallace, Daria J. Hazuda, Joan D. Ellis, Kara A. Stillmock, and Joseph P. Vacca

Subjects
education, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, HIV Integrase, Biochemistry, Virus, Inhibitory Concentration 50, Structure-Activity Relationship, Pharmacokinetics, Drug Discovery, Structure–activity relationship, Animals, Humans, HIV Integrase Inhibitors, Naphthyridines, Molecular Biology, Cells, Cultured, chemistry.chemical_classification, biology, Organic Chemistry, biology.organism_classification, Virology, humanities, In vitro, Integrase, Rats, Enzyme, chemistry, Enzyme inhibitor, Lentivirus, Mutation, biology.protein, Molecular Medicine
Abstract

A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.

Published
2006

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