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13 results on '"Maria S. Brown"'

2. Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form

Author

Taegyo Lee, Richard A. Wisdom, Amber M. Johnson, Kevin M. Knopf, Giselle P. Reyes, Bryan Li, Ruggeri Sally G, Maria S. Brown, Gerald A. Weisenburger, Lulin Wei, Adam E. Goetz, Cuong V. Lu, Kris N. Jones, Angela L. A. Puchlopek-Dermenci, Michaella A. Caporello, Samir A. Kulkarni, Mengtan Zhang, and Javier Magano

Subjects
chemistry.chemical_classification, Enzyme, Bicyclic molecule, Chemistry, Organic Chemistry, Moiety, Identification (biology), Amine gas treating, Physical and Theoretical Chemistry, Combinatorial chemistry
Published
2021

3. Late-Stage Lead Diversification Coupled with Quantitative Nuclear Magnetic Resonance Spectroscopy to Identify New Structure–Activity Relationship Vectors at Nanomole-Scale Synthesis: Application to Loratadine, a Human Histamine H1 Receptor Inverse Agonist

Author

Dennis Hyek, Jinshan Chen, R. Scott Obach, Melissa Wagenaar, Mark W. Bundesmann, Asser Bassyouni, Jeremy T. Starr, Maria S. Brown, Stephen Jenkinson, Manjinder S. Lall, Gregory Ciszewski, James Bradow, Gregory S. Walker, Senliang Pan, Douglas K. Spracklin, Bo Liu, Neal W. Sach, Daniel J Smaltz, Anne E. Hagen, and Usa Reilly

Subjects
0303 health sciences, Chemistry, Nuclear magnetic resonance spectroscopy, Histamine H1 receptor, Loratadine, Histamine H1 Antagonists, Tandem mass spectrometry, 01 natural sciences, Combinatorial chemistry, Chemical space, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, Drug Discovery, medicine, Molecular Medicine, Structure–activity relationship, Inverse agonist, 030304 developmental biology, medicine.drug
Abstract

An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 μmol). The approach delivers multiple analogues from a single lead at nanomole-scale amounts as DMSO-d6 stock solutions with a known structure and concentration for in vitro pharmacology and absorption, distribution, metabolism, and excretion testing. To demonstrate the feasibility of this approach, we have used the antihistamine agent loratadine (1). Twenty-six analogues of loratadine were isolated and fully characterized by NMR. Informative SAR analogues were identified, which display potent affinity for the human histamine H1 receptor and improved metabolic stability.

Published
2020

4. Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189

Author

Michael Aaron Brodney, Michael De Vivo, Ann S. Wright, Stephen Jenkinson, Shawn D. Doran, Patrick Robert Verhoest, Maria S. Brown, Gregory S. Walker, Christopher John Helal, Antonia F. Stepan, Travis T. Wager, R. Scott Obach, Ethan Lawrence Fisher, Tuan P. Tran, Bethany L. Kormos, Raman Sharma, Cheng Chang, Edward X. Yang, Rebecca E. O’Connor, and David Karanian

Subjects
0301 basic medicine, Pharmacology, 010402 general chemistry, 01 natural sciences, Biochemistry, 03 medical and health sciences, late-stage oxidation, Drug Discovery, drug−drug interactions, Liver microsomes, chemistry.chemical_classification, biology, Chemistry, Drug discovery, Organic Chemistry, Phosphodiesterase, Cytochrome P450, renal clearance, Featured Letter, 0104 chemical sciences, 030104 developmental biology, Enzyme, Microsome, biology.protein, Phosphodiesterase 2, PDE2, liver microsomes, Clearance
Abstract

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug–drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C–H diversification methods to drug discovery.

Published
2017

5. Industrial Carbonyl Reduction

Author

John W. Wong, Thomas S. Moody, Jeremy Steflik, Maria S. Brown, Owen W. Gooding, Gjalt W. Huisman, David Mangan, Carlos A. Martinez, Jack Liang, Michael Paul Burns, Adam A. Smogowicz, and Katarina S. Midelfort

Subjects
Chemistry, Carbonyl reduction, Organic chemistry, Photochemistry
Published
2012

8. Biosynthesis of the Shikimate-derived Starter Unit of the Immunosuppressant Ascomycin: Stereochemistry of the 1,4-Conjugate Elimination

Author

Sandeep Handa, Heinz G. Floss, Kevin A. Reynolds, Hamish A. I. McArthur, Kimberlee K. Wallace, and Maria S. Brown

Subjects
Pharmacology, Molecular Structure, Stereochemistry, Streptomycetaceae, Stereoisomerism, Metabolism, Biology, biology.organism_classification, Streptomyces, Tacrolimus, chemistry.chemical_compound, Biosynthesis, chemistry, Drug Discovery, medicine, Ascomycin, Streptomyces hygroscopicus, Immunosuppressive Agents, medicine.drug, Conjugate
Published
1997

9. Production of Tuberactinamine A by Streptomyces griseoverticillatus var. tuberacticus NRRL 3482 Fed with (S)-2-Aminoethyl-L-cysteine

Author

T. Kevin Murphy, Brook Knight Morse, John W. Wong, Richard Gerald Wax, Hamish A. I. McArthur, Gagne John William, Adam A. Smogowicz, Matt H. Narrol, Maria S. Brown, David Austen Perry, and Ellen L. McCormick

Subjects
Protein Synthesis Inhibitors, Pharmacology, biology, Streptomycetaceae, Stereochemistry, biology.organism_classification, Streptomyces, chemistry.chemical_compound, Biosynthesis, chemistry, Fermentation, Drug Discovery, Botany, Enviomycin, Cysteine, Actinomycetales, Bacteria, Antibacterial agent
Published
1997

10. Production of 6-deoxy-13-cyclopropyl-erythromycin B by Saccharopolyspora erythraea NRRL 18643

Author

Hamish A. I. McArthur, Ellen L. McCormick, Mike Pacey, Thomas N. O'Connell, John C. Ruddock, John P. Dirlam, Paul A. Murphy, Maria S. Brown, Brook Knight Morse, Richard Gerald Wax, and Dianne M. Rescek

Subjects
Cyclopropanes, Pseudonocardiaceae, Magnetic Resonance Spectroscopy, Stereochemistry, Carboxylic acid, Microbial Sensitivity Tests, chemistry.chemical_compound, Drug Discovery, Antibacterial agent, Pharmacology, chemistry.chemical_classification, biology, ATP synthase, Molecular Structure, biology.organism_classification, Anti-Bacterial Agents, Erythromycin, 6-deoxy-13-cyclopropyl-erythromycin B, Aglycone, chemistry, Biochemistry, biology.protein, Saccharopolyspora erythraea, Macrolides, Bacteria, Saccharopolyspora
Abstract

Cyclopropane carboxylic acid was fed to Saccharopolyspora erythraea NRRL 18643 (6-deoxyerythromycin producer), resulting in the production of 6-deoxy-13-cyclopropyl-erythromycin B. These studies provide further evidence that deoxyerythronolide B synthase has a relaxed specificity for the starter unit.

Published
1999

11. Stereochemical Analyses of the Streptomyces hygroscopicus var. ascomyceticus Type-II Dehydroquinate Dehydratase and Evidence for a Role of the Enzyme in the Biosynthesis of the Shikimate-Derived Moiety of Ascomycin

Author

Claudio D. Denoya, Maria S. Brown, Hamish A. I. McArthur, Kevin A. Reynolds, Yuko M. Lindsay, and Galina Florova

Subjects
chemistry.chemical_classification, biology, Stereochemistry, Chemistry, Organic Chemistry, biology.organism_classification, chemistry.chemical_compound, Enzyme, Biochemistry, Biosynthesis, Dehydratase, medicine, Moiety, Ascomycin, Streptomyces hygroscopicus, medicine.drug
Published
1998

12. Selective Production of Capreomycins through Mutation and Medium Development

Author

H. A. I. Mcarthur, Brook Knight Morse, A. E. Doro, Richard Gerald Wax, Maria S. Brown, and T. K. Murphy

Subjects
Pharmacology, biology, biology.organism_classification, Medium development, Streptomyces, Microbiology, Cell biology, Fermentation, Mutation, Drug Discovery, Mutation (genetic algorithm), Capreomycin, Antibiotics, Antitubercular, Chromatography, High Pressure Liquid, Antibacterial agent
Published
1997

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