Search

Your search keyword '"Brian A. Chauder"' showing total 5 results
Start Over Author "Brian A. Chauder" Journal journal of medicinal chemistry
5 results on '"Brian A. Chauder"'

1. Fragment-Based Screening of the Bromodomain of ATAD2

Author

Brian A. Chauder, Stephen W. Fesik, Jason Phan, and Mary J. Harner

Subjects
Magnetic Resonance Spectroscopy, Brief Article, Chemistry, Pharmaceutical, Molecular Conformation, Antineoplastic Agents, Crystallography, X-Ray, Ligands, DNA-binding protein, Molecular conformation, Protein structure, Fragment (logic), X ray methods, Neoplasms, Drug Discovery, Humans, Adenosine Triphosphatases, Binding Sites, Extramural, Chemistry, Protein Structure, Tertiary, 3. Good health, Bromodomain, DNA-Binding Proteins, Kinetics, Biochemistry, ATPases Associated with Diverse Cellular Activities, Molecular Medicine
Abstract

Cellular and genetic evidence suggest that inhibition of ATAD2 could be a useful strategy to treat several types of cancer. To discover small-molecule inhibitors of the bromodomain of ATAD2, we used a fragment-based approach. Fragment hits were identified using NMR spectroscopy, and ATAD2 was crystallized with three of the hits identified in the fragment screen.

Published
2014

2. Discovery of Potent Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods and Structure-Based Design

Author

Taekyu Lee, Stephen W. Fesik, Pedro M. Garcia-Barrantes, Edward T. Olejniczak, Jason P. Burke, Bin Zhao, Brian A. Chauder, Anders Friberg, R. Nathan Daniels, Dominico Vigil, and DeMarco V. Camper

Subjects
Indoles, Magnetic Resonance Spectroscopy, Myeloid, Databases, Factual, Apoptosis Inhibitor, Cell, bcl-X Protein, Antineoplastic Agents, Crystallography, X-Ray, Ligands, Small Molecule Libraries, Structure-Activity Relationship, Molecular recognition, Fragment (logic), hemic and lymphatic diseases, Drug Discovery, medicine, Humans, Molecular Structure, Chemistry, medicine.disease, Molecular biology, Molecular Docking Simulation, Dissociation constant, Leukemia, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Biochemistry, Apoptosis, Drug Design, Myeloid Cell Leukemia Sequence 1 Protein, Molecular Medicine, Protein Binding
Abstract

Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of

Published
2012

3. Discovery of Bioavailable 4,4-Disubstituted Piperidines as Potent Ligands of the Chemokine Receptor 5 and Inhibitors of the Human Immunodeficiency Virus-1

Author

Pat Wheelan, Brian A. Chauder, Christian Watson, Terrence Peter Kenakin, Robert M. Ferris, Cecilia S. Koble, Deborah K. Jones-Hertzog, Michael Youngman, Hanbiao Yang, Christopher J Aquino, Felix Deanda, and Wieslaw M. Kazmierski

Subjects
Molecular Structure, Receptors, CCR5, Bicyclic molecule, Stereochemistry, medicine.drug_class, Chemistry, Drug Evaluation, Preclinical, Carboxamide, Ligands, Antiviral Agents, Chemical synthesis, Virus, In vitro, Structure-Activity Relationship, Chemokine receptor, Piperidines, Biochemistry, In vivo, Drug Discovery, HIV-1, medicine, Molecular Medicine, Structure–activity relationship
Abstract

We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.

Published
2008

4. Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile

Author

Jennifer Poole Peckham, Don L. Anderson, Christian Watson, Brian Andrew Chauder, Michael Youngman, Terrence Peter Kenakin, Maggie S. McIntyre, Maosheng Duan, Wieslaw M. Kazmierski, Robert G. Ferris, Andrew Spaltenstein, Pat Wheelan, Christopher Joseph Aquino, Cecilia S. Koble, Dan G. Lang, Mary Beth Wire, and Angilique Svolto

Subjects
Stereochemistry, Anti-HIV Agents, hERG, Substituent, CCR5 receptor antagonist, chemistry.chemical_compound, Chemokine receptor, Structure-Activity Relationship, Dogs, Piperidines, Drug Discovery, Potency, Structure–activity relationship, Animals, Humans, Structural motif, chemistry.chemical_classification, Sulfonamides, biology, Haplorhini, Ether-A-Go-Go Potassium Channels, Sulfonamide, Rats, chemistry, Area Under Curve, Drug Design, CCR5 Receptor Antagonists, biology.protein, HIV-1, Molecular Medicine, Benzimidazoles, Azabicyclo Compounds, Tropanes
Abstract

We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).

Published
2011

Catalog

Books, media, physical & digital resources
See catalog results