Robert G. Gentles

Bristol-Myers Squibb (United States)

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Min Ding

East China University of Science and Technology

Susan B. Roberts

Bristol-Myers Squibb (United States)

Xiaofan Zheng

Blood Center of Zhejiang Province

Brett R. Beno

Bristol-Myers Squibb (United States)

Karen Rigat

Bristol-Myers Squibb (United States)

Michael A. Poss

Bristol-Myers Squibb (United States)

Ying-Kai Wang

Bristol-Myers Squibb (United States)

John F. Kadow

Bristol-Myers Squibb (United States)

Lenore A. Pelosi

Bristol-Myers Squibb (United States)

Mengping Liu

University of Hong Kong

Cooperative Institutions

Bristol-Myers Squibb (United States)

160

Bristol-Myers Squibb (Germany)

110

Park University

Grupo Lederval (Spain)

Abbott Fund

Abbott (United States)

Eli Lilly (United States)

Yale University

AbbVie (United States)

Harvard University

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CCDC 1508841: Experimental Crystal Structure Determination

The Cambridge Structural Database (2016)

Mendi A. Higgins Lawrence R. Marcin F. Christopher Zusi Robert G. Gentles Min Ding

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc1mn29n

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Citations (0)

Initial SAR studies on apamin-displacing 2-aminothiazole blockers of calcium-activated small conductance potassium channels

Bioorganic & Medicinal Chemistry Letters (2008)

Robert G. Gentles Katherine A. Grant-Young Shuanghua Hu Yazhong Huang Michael A. Poss

Apamin

Calcium-activated potassium channel

SK channel

Potassium channel blocker

Thallium

10.1016/j.bmcl.2008.08.023

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Citations (43)

Isolation and characterization of oligodeoxynucleotides containing dG-N²-AAF oxidation products of dG-C8-AF

Carcinogenesis (1991)

Shinya Shibutani Robert G. Gentles Francis Johnson Arthur P. Grollman

Decadeoxynudeotides containing N-(deoxyguanosine-N2-yl)-2-acetylaminofluorene (dG-N2-AAF) and three recently described products of oxidation of N-{deoxyguanosine-8-yl)-2-aminofluorene (dG-C8-AF) were isolated and characterized. dG-N2-AAF was synthesized; its structure was established by mass spectroscopic and 1H-NMR analysis. Decadeoxynudeotides containing dG-N2-AAF and dG-C8-AAF were prepared by permitting d(CACTAGTCAC) to react with N-acetoxy-AAF and separating the products by HPLC. The decamer containing dG-C8-AAF was incubated under aerobic alkaline conditions. In the presence of 2-mercaptoethanol, the adduct is deacetylated; in the absence of antioxidant, decamers bearing oxidation products are formed. Homogeneity of the modified oligomers was established by polyacrylamide gel electrophoresis. The modified oligodeoxy- nucleotides will be used to introduce dG-N2-aminofluorene adducts and oxidative lesions, site-specifically, into DNA, thereby to correlate these adducts with their mutagenic properties.

Deoxyguanosine

2-Acetylaminofluorene

10.1093/carcin/12.5.813

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Citations (40)

Synthesis and evaluation of potent pyrrolidine H3 antagonists

Bioorganic & Medicinal Chemistry Letters (2002)

Anil Vasudevan Scott E. Conner Robert G. Gentles Ramin Faghih Huaqing Liu

Moiety

Pyrrolidine

Imidazole

10.1016/s0960-894x(02)00685-6

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Citations (21)

Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase

Journal of Medicinal Chemistry (2014)

Robert G. Gentles Min Ding John A. Bender Carl P. Bergstrom Katharine Grant-Young

Described herein are structure–activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

Piperazine

NS5B

Membrane permeability

Structure–activity relationship

10.1021/jm4016894

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Citations (91)

Combinatorial Chemistry Edited by Hicham Fenniri. Oxford University Press, Inc., New York. 2000. xxxii + 476 pp. 19 × 24.5 cm. ISBN 0-19-963754-7. $70.00 (paperback).

Journal of Medicinal Chemistry (2001)

Robert G. Gentles

ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTCombinatorial Chemistry Edited by Hicham Fenniri. Oxford University Press, Inc., New York. 2000. xxxii + 476 pp. 19 × 24.5 cm. ISBN 0-19-963754-7. $70.00 (paperback).Robert G. GentlesView Author Information Senior Group Leader Medicinal Chemistry Technologies Global Pharmaceutical Research and Development Abbott Laboratories Abbott Park, Illinois 60044-3500Cite this: J. Med. Chem. 2001, 44, 24, 4306Publication Date (Web):September 29, 2001Publication History Published online29 September 2001Published inissue 1 November 2001https://pubs.acs.org/doi/10.1021/jm010342vhttps://doi.org/10.1021/jm010342vbook-reviewACS PublicationsCopyright © 2001 American Chemical SocietyRequest reuse permissionsArticle Views34Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Combinatorial synthesis,Students Get e-Alerts

10.1021/jm010342v

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Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors

Journal of Pharmacology and Experimental Therapeutics (2015)

Andrew Alt Annapurna Pendri R.L. Bertekap Guoping Li Yulia Benitex

The muscarinic acetylcholine receptor subtype 1 (M1) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer's disease. Indeed, the M1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer's disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M2 and M3. Therefore, drug discovery efforts targeting the M1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M1 receptor ligands have been described, which exhibit excellent selectivity for M1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-[1,4'-bipiperidine]-1'-carboxylate). Despite their selectivity for the M1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M1 receptor-targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M1 receptor selective activators.

Functional selectivity

10.1124/jpet.115.226910

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Citations (39)

Ligand-induced changes in hepatitis C virus NS5B polymerase structure

Antiviral Research (2010)

Karen Rigat Yi Wang Thomas W. Hudyma Min Ding Xiaofan Zheng

NS5B

10.1016/j.antiviral.2010.08.014

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Citations (28)

Aerial Oxidation of Acetylaminofluorene-Derived DNA Adducts

Springer eBooks (1990)

Shinya Shibutani Robert G. Gentles Francis Johnson

Solvolysis

10.1007/978-1-4615-3800-4_12

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Citations (5)

Screening and Characterization of Reactive Compounds with In Vitro Peptide-Trapping and Liquid Chromatography/High-Resolution Accurate Mass Spectrometry

SLAS DISCOVERY (2013)

Cong Wei Louis S. Chupak Thomas M. Philip Benjamin M. Johnson Robert G. Gentles

The present study describes a novel methodology for the detection of reactive compounds using in vitro peptide-trapping and liquid chromatography-high-resolution accurate mass spectrometry (LC-HRMS). Compounds that contain electrophilic groups can covalently bind to nucleophilic moieties in proteins and form adducts. Such adducts are thought to be associated with drug-mediated toxicity and therefore represent potential liabilities in drug discovery programs. In addition, reactive compounds identified in biological screening can be associated with data that can be misinterpreted if the reactive nature of the compound is not appreciated. In this work, to facilitate the triage of hits from high-throughput screening (HTS), a novel assay was developed to monitor the formation of covalent peptide adducts by compounds suspected to be chemically reactive. The assay consists of in vitro incubations of test compounds (under conditions of physiological pH) with synthetically prepared peptides presenting a variety of nucleophilic moieties such as cysteine, lysine, histidine, arginine, serine, and tyrosine. Reaction mixtures were analyzed using full-scan LC-HRMS, the data were interrogated using postacquisition data mining, and modified amino acids were identified by subsequent LC-HRMS/mass spectrometry. The study demonstrated that in vitro nucleophilic peptide trapping followed by LC-HRMS analysis is a useful approach for screening of intrinsically reactive compounds identified from HTS exercises, which are then removed from follow-up processes, thus obviating the generation of data from biochemical activity assays.

Reactive intermediate

10.1177/1087057113492852

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Citations (10)