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Lesinurad

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https://www.readbyqxmd.com/read/27854343/discovery-of-a-flexible-triazolylbutanoic-acid-as-a-highly-potent-uric-acid-transporter-1-urat1-inhibitor
#1
He Tian, Wei Liu, Zhixing Zhou, Qian Shang, Yuqiang Liu, Yafei Xie, Changying Liu, Weiren Xu, Lida Tang, Jianwu Wang, Guilong Zhao
In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH₂, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 μM against human URAT1 for 1q vs 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity...
November 16, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27849193/lesinurad-zurampic-for-gout-associated-hyperuricemia
#2
(no author information available yet)
No abstract text is available yet for this article.
November 21, 2016: Medical Letter on Drugs and Therapeutics
https://www.readbyqxmd.com/read/27843295/effects-of-renal-function-on-pharmacokinetics-and-pharmacodynamics-of-lesinurad-in-adult-volunteers
#3
Michael Gillen, Shakti Valdez, Dongmei Zhou, Bradley Kerr, Caroline A Lee, Zancong Shen
INTRODUCTION: Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function. METHODS: Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60-89 mL/min; N=8), moderate (eCrCl 30-59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27826183/supratherapeutic-dose-evaluation-and-effect-of-lesinurad-on-cardiac-repolarization-a-thorough-qt-qtc-study
#4
Zancong Shen, Michael Gillen, Kathy Tieu, Mai Nguyen, Erin Harmon, David M Wilson, Bradley Kerr, Caroline A Lee
INTRODUCTION: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and Europe for treatment of gout in combination with a xanthine oxidase inhibitor. A maximum tolerated dose study was conducted to determine the lesinurad supratherapeutic dose, followed by a thorough QTc study to characterize the effect of lesinurad on cardiac repolarization. METHODS: The maximum tolerated dose study was a randomized, double-blind, placebo-controlled, single-ascending dose study that enrolled 35 healthy men and women...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27821644/lesinurad-in-combination-with-allopurinol-a-randomised-double-blind-placebo-controlled-study-in-patients-with-gout-with-inadequate-response-to-standard-of-care-the-multinational-clear-2-study
#5
Thomas Bardin, Robert T Keenan, Puja P Khanna, Jeff Kopicko, Maple Fung, Nihar Bhakta, Scott Adler, Chris Storgard, Scott Baumgartner, Alexander So
OBJECTIVES: Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. METHODS: Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6...
November 7, 2016: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/27733209/erratum-to-lesinurad-a-novel-oral-compound-for-gout-acts-to-decrease-serum-uric-acid-through-inhibition-of-urate-transporters-in-the-kidney
#6
Jeffrey N Miner, Philip K Tan, David Hyndman, Sha Liu, Cory Iverson, Payal Nanavati, David T Hagerty, Kimberly Manhard, Zancong Shen, Jean-Luc Girardet, Li-Tain Yeh, Robert Terkeltaub, Barry Quart
No abstract text is available yet for this article.
October 12, 2016: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/27716403/lesinurad-a-novel-oral-compound-for-gout-acts-to-decrease-serum-uric-acid-through-inhibition-of-urate-transporters-in-the-kidney
#7
Jeffrey Miner, Philip K Tan, David Hyndman, Sha Liu, Cory Iverson, Payal Nanavati, David T Hagerty, Kimberly Manhard, Zancong Shen, Jean-Luc Girardet, Li-Tain Yeh, Robert Terkeltaub, Barry Quart
BACKGROUND: Excess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug-drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout...
October 3, 2016: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/27633583/discovery-of-flexible-naphthyltriazolylmethane-based-thioacetic-acids-as-highly-active-uric-acid-transporter-1-urat1-inhibitors-for-the-treatment-of-hyperuricemia-of-gout
#8
Xiansheng Zhang, Jingwei Wu, Wei Liu, Yuqiang Liu, Yafei Xie, Qian Shang, Zhixing Zhou, Weiren Xu, Lida Tang, Jianwu Wang, Guilong Zhao
BACKGROUND: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. OBJECTIVE: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor...
September 15, 2016: Medicinal Chemistry
https://www.readbyqxmd.com/read/27564409/lesinurad-combined-with-allopurinol-randomized-double-blind-placebo-controlled-study-in-gout-subjects-with-inadequate-response-to-standard-of-care-allopurinol-a-us-based-study
#9
Kenneth G Saag, David Fitz-Patrick, Jeff Kopicko, Maple Fung, Nihar Bhakta, Scott Adler, Chris Storgard, Scott Baumgartner, Michael A Becker
OBJECTIVE: Lesinurad is a selective uric acid reabsorption inhibitor for treatment of gout in combination with xanthine oxidase inhibitors. CLEAR 1 (Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders) was a 12-month, randomized, phase-III trial of daily lesinurad (200-mg or 400-mg orally) added to allopurinol in subjects with serum urate (sUA) above <6.0 mg/dL target. METHODS: Subjects on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA ≥6...
August 26, 2016: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/27509346/-an-update-on-gout-diagnostic-approach-treatment-and-comorbidity
#10
Magnus Diller, Martin Fleck
Muskuloskeletal ultrasound and dual-energy-CT (DECT) findings are increasingly relevant for the establishment of the diagnosis of gout, and are therefore incorporated into the novel ACR / EULAR classification criteria. Canakinumab, a monoclonal antibody directed against interleukin-1β (IL-1β) has been approved in 2013 for the treatment of acute gout and for prophylaxis of flares. In patients demonstrating an inadequate response upon treatment with allopurinol or febuxostat, combination therapy with lesinurad might reduce uric acid levels to the target of < 6 mg / dl (< 5 mg / dl in tophaceous gout)...
August 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27493693/treatment-of-hyperuricemia-in-gout-current-therapeutic-options-latest-developments-and-clinical-implications
#11
REVIEW
Sebastian E Sattui, Angelo L Gaffo
Despite being the most common type of inflammatory arthritis, gout is often poorly managed. Except for febuxostat and pegloticase, research in new therapeutic agents for the management of hyperuricemia in gout remained insufficient for several decades. With emerging evidence of possible roles of hyperuricemia in cardiometabolic comorbidities, as well as more convincing evidence regarding poor outcomes (e.g. disability, recurrent hospital admissions) in patients with uncontrolled gout, several agents are current under development...
August 2016: Therapeutic Advances in Musculoskeletal Disease
https://www.readbyqxmd.com/read/27438964/justification-of-drug-product-dissolution-rate-and-drug-substance-particle-size-specifications-based-on-absorption-pbpk-modeling-for-lesinurad-immediate-release-tablets
#12
Xavier J H Pepin, Talia R Flanagan, David J Holt, Anna Eidelman, Don Treacy, Colin E Rowlings
In silico absorption modeling has been performed, to assess the impact of in vitro dissolution on in vivo performance for ZURAMPIC (lesinurad) tablets. The dissolution profiles of lesinurad tablets generated using the quality control method were used as an input to a GastroPlus model to estimate in vivo dissolution in the various parts of the GI tract and predict human exposure. A model was set up, which accounts for differences of dosage form transit, dissolution, local pH in the GI tract, and fluid volumes available for dissolution...
September 6, 2016: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27303095/mepolizumab
#13
Dennis J Cada, Ross J Bindler, Danial E Baker
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line...
May 2016: Hospital Pharmacy
https://www.readbyqxmd.com/read/27303081/patiromer
#14
Dennis J Cada, Jessica Dang, Danial E Baker
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line...
April 2016: Hospital Pharmacy
https://www.readbyqxmd.com/read/27156944/eluxadoline-lesinurad-and-idarucizumab
#15
Daniel A Hussar, Maggie Gandhi
No abstract text is available yet for this article.
May 2016: Journal of the American Pharmacists Association: JAPhA
https://www.readbyqxmd.com/read/26951201/in-vitro-and-in-vivo-interaction-studies-between-lesinurad-a-selective-urate-reabsorption-inhibitor-and-major-liver-or-kidney-transporters
#16
Zancong Shen, Li-Tain Yeh, Kathleen Wallach, Nanqun Zhu, Brad Kerr, Michael Gillen
BACKGROUND AND OBJECTIVES: Lesinurad is a selective uric acid reabsorption inhibitor (SURI) under investigation for the treatment of gout. This study elucidated the interaction of lesinurad with major liver and kidney transporters in vitro and evaluated the drug-drug interactions (DDIs) of lesinurad and atorvastatin, metformin, and furosemide in clinical studies. METHODS: Lesinurad interaction with membrane transporters was evaluated in validated transporter-expressing cell systems and analyzed by liquid scintillation counting...
June 2016: Clinical Drug Investigation
https://www.readbyqxmd.com/read/26947439/treatment-of-tophaceous-gout-when-medication-is-not-enough
#17
REVIEW
Isaac R Kasper, Matthew D Juriga, John M Giurini, Robert H Shmerling
OBJECTIVES: To review the literature concerning surgical intervention of tophaeceous gout and propose clinical circumstances for when it may be considered. INTRODUCTION: Tophi develop in approximately 12-35% of patients with gout. Tophaceous disease is usually preventable given the availability of effective urate lowering therapies (ULT) including allopurinol, febuxostat, probenecid, lesinurad, and pegloticase. Despite medical therapy, there remains a subset of patients who develop significant complications of tophi including infection, ulceration, and entrapment neuropathy...
June 2016: Seminars in Arthritis and Rheumatism
https://www.readbyqxmd.com/read/26908998/pharmaceutical-approval-update
#18
Chris Fellner
Lesinurad (Zurampic) for gout-related hyperuricemia; selexipag (Uptravi) for pulmonary arterial hypertension; sugammadex (Bridion) to reverse neuromuscular blockade after surgery; and alectinib (Alecensa) for lung cancer.
February 2016: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/26861027/lesinurad-first-global-approval
#19
Sheridan M Hoy
Lesinurad (ZURAMPIC(®)) is an oral urate-anion exchanger transporter 1 (URAT1) inhibitor developed by Ardea Biosciences (a subsidiary of AstraZeneca) for the treatment of hyperuricaemia associated with gout. It reduces serum uric acid (sUA) levels by inhibiting the function of the transporter proteins (URAT1 and organic anion transporter 4) involved in uric acid reabsorption in the kidney. In December 2015, lesinurad was approved in the USA as combination therapy with a xanthine oxidase inhibitor for the treatment of hyperuricaemia associated with gout in patients who have not achieved sUA target levels with a xanthine oxidase inhibitor alone...
March 2016: Drugs
https://www.readbyqxmd.com/read/26823621/secukinumab
#20
Dennis J Cada, Danial E Baker, Shannon G Panther, Kyle Ingram PharmD
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line...
September 2015: Hospital Pharmacy
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