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Author Adrian S Ray

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Species differences in liver accumulation and metabolism of nucleotide prodrug sofosbuvir.

Ting Wang, Darius Babusis, Yeojin Park, Congrong Niu, Cynthia Kim, Xiaofeng Zhao, Bing Lu, Bin Ma, Robert C Muench, Diana Sperger, Adrian S Ray, Eisuke Murakami,

Sofosbuvir (SOF) is a nucleotide prodrug which has been used as a backbone for the clinical treatment of hepatitis C viral infection. Because sofosbuvir undergoes complex first pass metabolism, including metabolic activation to form its pharmacologically active triphosphate (GS-331007-TP) to inhibit the viral RNA polymerase in the liver, it is ... Read more >>

Drug Metab. Pharmacokinet. (Drug metabolism and pharmacokinetics)
[2020, 35(3):334-340]

Cited: 0 times

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Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton's tyrosine kinase reveals differences in on - and off - target inhibition.

Albert Liclican, Loredana Serafini, Weimei Xing, Gregg Czerwieniec, Bart Steiner, Ting Wang, Katherine M Brendza, Justin D Lutz, Kathleen S Keegan, Adrian S Ray, Brian E Schultz, Roman Sakowicz, Joy Y Feng,

BACKGROUND:Bruton's tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR) pathway and a clinically validated target for small molecule inhibitors such as ibrutinib in the treatment of B-cell malignancies. Tirabrutinib (GS-4059/ONO-4059) is a selective, once daily, oral BTK inhibitor with clinical activity against many relapsed/refractory B-cell malignancies. ... Read more >>

Biochim Biophys Acta Gen Subj (Biochimica et biophysica acta. General subjects)
[2020, 1864(4):129531]

Cited: 1 time

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Acetyl-CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents.

Leigh Goedeke, Jamie Bates, Daniel F Vatner, Rachel J Perry, Ting Wang, Ricardo Ramirez, Li Li, Matthew W Ellis, Dongyan Zhang, Kari E Wong, Carine Beysen, Gary W Cline, Adrian S Ray, Gerald I Shulman,

Pharmacologic inhibition of acetyl-CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for nonalcoholic fatty liver disease (NAFLD) through simultaneous inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. However, the effects of ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo are ... Read more >>

Hepatology (Hepatology (Baltimore, Md.))
[2018, 68(6):2197-2211]

Cited: 19 times

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Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma.

James S V Lally, Sarani Ghoshal, Danielle K DePeralta, Omeed Moaven, Lan Wei, Ricard Masia, Derek J Erstad, Naoto Fujiwara, Vivian Leong, Vanessa P Houde, Alexander E Anagnostopoulos, Alice Wang, Lindsay A Broadfield, Rebecca J Ford, Robert A Foster, Jamie Bates, Hailing Sun, Ting Wang, Henry Liu, Adrian S Ray, Asish K Saha, Jeremy Greenwood, Sathesh Bhat, Geraldine Harriman, Wenyan Miao, Jennifer L Rocnik, William F Westlin, Paola Muti, Theodoros Tsakiridis, H James Harwood, Rosana Kapeller, Yujin Hoshida, Kenneth K Tanabe, Gregory R Steinberg, Bryan C Fuchs,

The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss-of-function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites on ... Read more >>

Cell Metab. (Cell metabolism)
[2019, 29(1):174-182.e5]

Cited: 18 times

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Nucleotide Prodrug Containing a Nonproteinogenic Amino Acid To Improve Oral Delivery of a Hepatitis C Virus Treatment.

Joy Y Feng, Ting Wang, Yeojin Park, Darius Babusis, Gabriel Birkus, Yili Xu, Christian Voitenleitner, Martijn Fenaux, Huiling Yang, Stacey Eng, Neeraj Tirunagari, Thorsten Kirschberg, Aesop Cho, Adrian S Ray,

Delivery of pharmacologically active nucleoside triphosphate analogs to sites of viral infection is challenging. In prior work we identified a 2'-C-methyl-1'-cyano-7-deaza-adenosine C-nucleotide analog with desirable selectivity and potency for the treatment of hepatitis C virus (HCV) infection. However, the prodrug selected for clinical development, GS-6620, required a high dose for ... Read more >>

Antimicrob. Agents Chemother. (Antimicrobial agents and chemotherapy)
[2018, 62(8):]

Cited: 0 times

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Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance.

Maciej J Zamek-Gliszczynski, Mitchell E Taub, Paresh P Chothe, Xiaoyan Chu, Kathleen M Giacomini, Richard B Kim, Adrian S Ray, Sophie L Stocker, Jashvant D Unadkat, Matthias B Wittwer, Cindy Xia, Sook-Wah Yee, Lei Zhang, Yan Zhang, ,

This white paper provides updated International Transporter Consortium (ITC) recommendations on transporters that are important in drug development following the 3rd ITC workshop. New additions include prospective evaluation of organic cation transporter 1 (OCT1) and retrospective evaluation of organic anion transporting polypeptide (OATP)2B1 because of their important roles in drug ... Read more >>

Clin. Pharmacol. Ther. (Clinical pharmacology and therapeutics)
[2018, 104(5):890-899]

Cited: 15 times

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Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis.

Eric J Lawitz, Angie Coste, Fred Poordad, Naim Alkhouri, Nicole Loo, Bryan J McColgan, Jacqueline M Tarrant, Tuan Nguyen, Ling Han, Chuhan Chung, Adrian S Ray, John G McHutchison, G Mani Subramanian, Robert P Myers, Michael S Middleton, Claude Sirlin, Rohit Loomba, Edna Nyangau, Mark Fitch, Kelvin Li, Marc Hellerstein,

BACKGROUND & AIMS:Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH. METHODS:In an open-label prospective study, patients with NASH ... Read more >>

Clin. Gastroenterol. Hepatol. (Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association)
[2018, 16(12):1983-1991.e3]

Cited: 18 times

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ITC Commentary on Metformin Clinical Drug-Drug Interaction Study Design That Enables an Efficacy- and Safety-Based Dose Adjustment Decision.

Maciej J Zamek-Gliszczynski, Xiaoyan Chu, Jack A Cook, Joseph M Custodio, Aleksandra Galetin, Kathleen M Giacomini, Caroline A Lee, Mary F Paine, Adrian S Ray, Joseph A Ware, Matthias B Wittwer, Lei Zhang, ,

Metformin drug-drug interaction (DDI) studies are conducted during development of drugs that inhibit organic cation transporters and/or multidrug and toxin extrusion proteins (OCTs/MATEs). Monitoring solely changes in systemic exposure, the typical DDI study endpoint appears inadequate for metformin, which is metabolically stable, has poor passive membrane permeability, and undergoes transporter-mediated ... Read more >>

Clin. Pharmacol. Ther. (Clinical pharmacology and therapeutics)
[2018, 104(5):781-784]

Cited: 4 times

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Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease.

Maria L Agostini, Erica L Andres, Amy C Sims, Rachel L Graham, Timothy P Sheahan, Xiaotao Lu, Everett Clinton Smith, James Brett Case, Joy Y Feng, Robert Jordan, Adrian S Ray, Tomas Cihlar, Dustin Siegel, Richard L Mackman, Michael O Clarke, Ralph S Baric, Mark R Denison,

Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs in vitro and in a ... Read more >>

mBio (mBio)
[2018, 9(2):]

Cited: 144 times

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Transporter Expression in Noncancerous and Cancerous Liver Tissue from Donors with Hepatocellular Carcinoma and Chronic Hepatitis C Infection Quantified by LC-MS/MS Proteomics.

Sarah Billington, Adrian S Ray, Laurent Salphati, Guangqing Xiao, Xiaoyan Chu, W Griffith Humphreys, Mingxiang Liao, Caroline A Lee, Anita Mathias, Cornelis E C A Hop, Christopher Rowbottom, Raymond Evers, Yurong Lai, Edward J Kelly, Bhagwat Prasad, Jashvant D Unadkat,

Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous (C, n = 8) and adjacent noncancerous (NC, n = 33) liver tissues obtained from patients with chronic hepatitis C with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare ... Read more >>

Drug Metab. Dispos. (Drug metabolism and disposition: the biological fate of chemicals)
[2018, 46(2):189-196]

Cited: 3 times

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Beyond drug-drug interactions: effects of transporter inhibition on endobiotics, nutrients and toxins.

Eve-Irene Lepist, Adrian S Ray,

Membrane transport proteins play a central role in regulating the disposition of endobiotics, dietary nutrients and environmental toxins. The inhibition of transporters by drugs has potential physiologic consequences. The full extent of the effect of drugs on the function of transporters is poorly understood because only a small subset of ... Read more >>

Expert Opin Drug Metab Toxicol (Expert opinion on drug metabolism & toxicology)
[2017, 13(10):1075-1087]

Cited: 4 times

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Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.

Timothy P Sheahan, Amy C Sims, Rachel L Graham, Vineet D Menachery, Lisa E Gralinski, James B Case, Sarah R Leist, Krzysztof Pyrc, Joy Y Feng, Iva Trantcheva, Roy Bannister, Yeojin Park, Darius Babusis, Michael O Clarke, Richard L Mackman, Jamie E Spahn, Christopher A Palmiotti, Dustin Siegel, Adrian S Ray, Tomas Cihlar, Robert Jordan, Mark R Denison, Ralph S Baric,

Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) ... Read more >>

Sci Transl Med (Science translational medicine)
[2017, 9(396):]

Cited: 175 times

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GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses.

Michael K Lo, Robert Jordan, Aaron Arvey, Jawahar Sudhamsu, Punya Shrivastava-Ranjan, Anne L Hotard, Mike Flint, Laura K McMullan, Dustin Siegel, Michael O Clarke, Richard L Mackman, Hon C Hui, Michel Perron, Adrian S Ray, Tomas Cihlar, Stuart T Nichol, Christina F Spiropoulou,

GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola ... Read more >>

Sci Rep (Scientific reports)
[2017, 7:43395]

Cited: 70 times

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Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties.

Thorsten A Kirschberg, Sammy Metobo, Michael O Clarke, Vangelis Aktoudianakis, Darius Babusis, Ona Barauskas, Gabriel Birkus, Thomas Butler, Daniel Byun, Gregory Chin, Edward Doerffler, Thomas E Edwards, Martijn Fenaux, Rick Lee, Willard Lew, Michael R Mish, Eisuke Murakami, Yeojin Park, Neil H Squires, Neeraj Tirunagari, Ting Wang, Mark Whitcomb, Jie Xu, Huiling Yang, Hong Ye, Lijun Zhang, Todd C Appleby, Joy Y Feng, Adrian S Ray, Aesop Cho, Choung U Kim,

A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & Medicinal Chemistry Letters)
[2017, 27(8):1840-1847]

Cited: 0 times

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Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses.

Dustin Siegel, Hon C Hui, Edward Doerffler, Michael O Clarke, Kwon Chun, Lijun Zhang, Sean Neville, Ernest Carra, Willard Lew, Bruce Ross, Queenie Wang, Lydia Wolfe, Robert Jordan, Veronica Soloveva, John Knox, Jason Perry, Michel Perron, Kirsten M Stray, Ona Barauskas, Joy Y Feng, Yili Xu, Gary Lee, Arnold L Rheingold, Adrian S Ray, Roy Bannister, Robert Strickley, Swami Swaminathan, William A Lee, Sina Bavari, Tomas Cihlar, Michael K Lo, Travis K Warren, Richard L Mackman,

The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2017, 60(5):1648-1661]

Cited: 64 times

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Tenofovir alafenamide (TAF) does not deplete mitochondrial DNA in human T-cell lines at intracellular concentrations exceeding clinically relevant drug exposures.

Kirsten M Stray, Yeojin Park, Darius Babusis, Christian Callebaut, Tomas Cihlar, Adrian S Ray, Michel Perron,

HIV-infected patients treated with certain nucleoside reverse transcriptase inhibitors (NRTIs) have experienced adverse effects due to drug-related mitochondrial toxicity. Tenofovir alafenamide (TAF) is a novel prodrug of the NRTI tenofovir (TFV) with an improved safety profile compared to tenofovir disoproxil fumarate (TDF). Prior in vitro studies have demonstrated that the parent ... Read more >>

Antiviral Res. (Antiviral research)
[2017, 140:116-120]

Cited: 7 times

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Role of Mitochondrial Toxicity in BMS-986094-Induced Toxicity.

Joy Y Feng, Chin H Tay, Adrian S Ray,

Toxicol. Sci. (Toxicological sciences : an official journal of the Society of Toxicology)
[2017, 155(1):2]

Cited: 3 times

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Interaction of 2,4-Diaminopyrimidine-Containing Drugs Including Fedratinib and Trimethoprim with Thiamine Transporters.

Marilyn M Giacomini, Jia Hao, Xiaomin Liang, Jayaraman Chandrasekhar, Jolyn Twelves, J Andrew Whitney, Eve-Irene Lepist, Adrian S Ray,

Inhibition of thiamine transporters has been proposed as a putative mechanism for the observation of Wernicke's encephalopathy and subsequent termination of clinical development of fedratinib, a Janus kinase inhibitor (JAKi). This study aimed to determine the potential for other JAKi to inhibit thiamine transport using human epithelial colorectal adenocarcinoma (Caco-2) ... Read more >>

Drug Metab. Dispos. (Drug metabolism and disposition: the biological fate of chemicals)
[2017, 45(1):76-85]

Cited: 5 times

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Chemoprophylaxis With Oral Emtricitabine and Tenofovir Alafenamide Combination Protects Macaques From Rectal Simian/Human Immunodeficiency Virus Infection.

Ivana Massud, James Mitchell, Darius Babusis, Frank Deyounks, Adrian S Ray, James F Rooney, Walid Heneine, Michael D Miller, J Gerardo García-Lerma,

Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir that efficiently delivers tenofovir diphosphate to lymphoid cells following oral administration. We investigated whether the combination of TAF and emtricitabine (FTC) could prevent simian/human immunodeficiency virus (SHIV) infection in macaques to determine the potential use of TAF for pre-exposure prophylaxis (PrEP) ... Read more >>

J. Infect. Dis. (The Journal of infectious diseases)
[2016, 214(7):1058-1062]

Cited: 12 times

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Renal Transporter-Mediated Drug-Drug Interactions: Are They Clinically Relevant?

Eve-Irene Lepist, Adrian S Ray,

The kidney, through the distinct processes of passive glomerular filtration and active tubular secretion, plays an important role in the elimination of numerous endobiotics (eg, hormones, metabolites), toxins, nutrients, and drugs. Renal transport pathways mediating active tubular secretion and reabsorption in the proximal tubule are complex, involving apical and basolateral ... Read more >>

J Clin Pharmacol (Journal of clinical pharmacology)
[2016, 56 Suppl 7:S73-81]

Cited: 9 times

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Involvement of Drug Transporters in Organ Toxicity: The Fundamental Basis of Drug Discovery and Development.

Yaofeng Cheng, Ayman El-Kattan, Yan Zhang, Adrian S Ray, Yurong Lai,

Membrane transporters play a pivotal role in many organs to maintain their normal physiological functions and contribute significantly to drug absorption, distribution, and elimination. Knowledge gained from gene modified animal models or human genetic disorders has demonstrated that interruption of the transporter activity can lead to debilitating diseases or organ ... Read more >>

Chem. Res. Toxicol. (Chemical research in toxicology)
[2016, 29(4):545-563]

Cited: 5 times

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Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.

Travis K Warren, Robert Jordan, Michael K Lo, Adrian S Ray, Richard L Mackman, Veronica Soloveva, Dustin Siegel, Michel Perron, Roy Bannister, Hon C Hui, Nate Larson, Robert Strickley, Jay Wells, Kelly S Stuthman, Sean A Van Tongeren, Nicole L Garza, Ginger Donnelly, Amy C Shurtleff, Cary J Retterer, Dima Gharaibeh, Rouzbeh Zamani, Tara Kenny, Brett P Eaton, Elizabeth Grimes, Lisa S Welch, Laura Gomba, Catherine L Wilhelmsen, Donald K Nichols, Jonathan E Nuss, Elyse R Nagle, Jeffrey R Kugelman, Gustavo Palacios, Edward Doerffler, Sean Neville, Ernest Carra, Michael O Clarke, Lijun Zhang, Willard Lew, Bruce Ross, Queenie Wang, Kwon Chun, Lydia Wolfe, Darius Babusis, Yeojin Park, Kirsten M Stray, Iva Trancheva, Joy Y Feng, Ona Barauskas, Yili Xu, Pamela Wong, Molly R Braun, Mike Flint, Laura K McMullan, Shan-Shan Chen, Rachel Fearns, Swami Swaminathan, Douglas L Mayers, Christina F Spiropoulou, William A Lee, Stuart T Nichol, Tomas Cihlar, Sina Bavari,

The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. ... Read more >>

Nature (Nature)
[2016, 531(7594):381-385]

Cited: 229 times

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Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus.

Adrian S Ray, Marshall W Fordyce, Michael J M Hitchcock,

Despite substantial progress in the development of antiretroviral regimens that durably suppress Human Immunodeficiency Virus (HIV) infection, new agents that maintain high efficacy while further optimizing the safety of lifelong, chronic therapy are needed. Tenofovir alafenamide (TAF; formerly known as GS-7340) is a novel prodrug of the antiviral acyclic nucleoside ... Read more >>

Antiviral Res. (Antiviral research)
[2016, 125:63-70]

Cited: 85 times

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Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).

Xiaomin Liang, Huan-Chieh Chien, Sook Wah Yee, Marilyn M Giacomini, Eugene C Chen, Meiling Piao, Jia Hao, Jolyn Twelves, Eve-Irene Lepist, Adrian S Ray, Kathleen M Giacomini,

The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic ... Read more >>

Mol. Pharm. (Molecular pharmaceutics)
[2015, 12(12):4301-4310]

Cited: 22 times

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Synthesis of 1'-C-cyano pyrimidine nucleosides and characterization as HCV polymerase inhibitors.

Thorsten A Kirschberg, Michael Mish, Neil H Squires, Sebastian Zonte, Evangelos Aktoudianakis, Sammy Metobo, Thomas Butler, Xie Ju, Aesop Cho, Adrian S Ray, Choung U Kim,

Ribose modified 1'-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity. ... Read more >>

Nucleosides Nucleotides Nucleic Acids (Nucleosides, nucleotides & nucleic acids)
[2015, 34(11):763-785]

Cited: 2 times

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