Delving into the Latest Updates on Lesinurad with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Lesinurad (USAN/INN), Lesinurad Sodium, {[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

+ [3]

Target

URAT1

Mechanism

URAT1 inhibitors(Uric acid transporter 1 inhibitors)

Therapeutic Areas

Immune System DiseasesCongenital DisordersEndocrinology and Metabolic Disease+ [2]

Active Indication-

Inactive Indication

Chronic tophaceous goutGoutHyperuricemia

Originator Organization

Ardea Biosciences, Inc.

Active Organization-

Inactive Organization

Ardea Biosciences, Inc.

Grünenthal GmbH

Ironwood Pharmaceuticals, Inc.

Drug Highest PhaseWithdrawn

First Approval Date

US (22 Dec 2015),

GoutHyperuricemia

Regulation-

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Structure

Molecular FormulaC17H14BrN3O2S

InChIKeyFGQFOYHRJSUHMR-UHFFFAOYSA-N

CAS Registry878672-00-5

Non-interventional population-based prospective cohort study in multiple databases comparing patients with gout who initiate lesinurad in combination with an existing xanthine oxidase inhibitor (XOI) (lesinurad+XOI cohort) to a propensity score-matched cohort of similar patients from the same data source who continue treatment with XOI monotherapy (XOI mono cohort). Study will characterize the cardiovascular safety of lesinurad in combination with XOI in patients with gout aged 18+ years compared with similar patients who continue XOI monotherapy. Primary objective: to assess the relative incidence of major adverse cardiac events plus hospitalization for unstable angina (MACE+ events) in patients with gout in both cohorts. Secondary objectives: to describe the characteristics of the cohorts prior to matching; to assess the relative incidence of hospitalisation for acute kidney injury between the matched cohorts; to assess the relative incidence of individual MACE+ components in the matched cohorts.

Start Date29 Jan 2021

Sponsor / Collaborator

AstraZeneca PLC

NCT03272425 / CompletedPhase 1

A Randomized, Open-label, Replicate, Crossover, 4-period Study to Assess the Bioequivalence of Lesinurad/Allopurinol Fixed-dose Combination 200/300 mg Tablets From Ardea Biosciences, Inc. (Test Drug) Versus Lesinurad, 200 mg Tablet From AstraZeneca (Comparator 1) Coadministered With Zyloric®, Allopurinol 300 mg Tablet From Aspen Pharma Industria Farmaceutica Ltda. (Comparator 2) in Healthy Female and Male Adult Subjects, Under Fasting Conditions.

To assess the bioequivalence between lesinurad/allopurinol 200/300 FDC tablets and coadministered lesinurad and allopurinol tablets in the fasted state based on the pharmacokinetic (PK) evaluation of lesinurad and allopurinol in healthy adult subjects.

Start Date14 Aug 2017

Sponsor / Collaborator

Ardea Biosciences, Inc.

NCT03226899 / TerminatedPhase 4

A Phase 4, Study to Evaluate the Safety and Efficacy of Lesinurad 200 mg in Combination With a Xanthine Oxidase Inhibitor (XOI), Compared With an XOI Alone, in Subjects With Gout and Estimated Creatinine Clearance (eCrCl) 30 to <60 mL/Min Who Have Not Achieved Target Serum Uric Acid Levels (sUA) on an XOI Alone

This study evaluates the safety and efficacy of lesinurad administered with an XOI versus a placebo plus an XOI in gout participants who have moderate renal impairment and who are not at target level of serum urate (sUA).

Start Date19 Jul 2017

Sponsor / Collaborator

Ironwood Pharmaceuticals, Inc.

[+1]

100 Clinical Results associated with Lesinurad

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100 Translational Medicine associated with Lesinurad

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100 Patents (Medical) associated with Lesinurad

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145

Literatures (Medical) associated with Lesinurad

01 Nov 2024·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design, synthesis and bioactivity evaluation of isobavachin derivatives as hURAT1 inhibitors for hyperuricemia agents

Article

Author: Tian, Yuanxin ; Wu, Ting ; Chen, Xinhua ; Li, Zhonghuang ; Wan, Shanhe ; Zhao, Zean ; Luo, Jian ; Zhang, Jiajie ; Chen, Mengyu ; Chen, Jianjun ; Pang, Jianxin ; Luo, Jiajun

Previously, we reported a novel natural scaffold compound, isobavachin (4',7-dihydroxy-8-prenylflavanone), as a highly potent hURAT1 inhibitor with anti-hyperuricemia effect. However, the structure-activity relationship remains unknown and the poor pharmacokinetic (PK) parameters may limit further clinical use. Herein, a series of isobavachin derivatives were rationally designed and synthesized to explore the structure-activity relationship of isobavachin target hURAT1, and to improve their PK properties. Among them, compounds 15d, 15f, 15g, 27b and 27d showed promising hURAT1 inhibitory activities, which could comparable to that of isobavachin (IC₅₀ = 0.24 μM). In addition, 27b also inhibited another urate reabsorption transporter GLUT9 with an IC₅₀ of 4.47 μM. Compound 27b displayed greater urate-lowering activity in a hyperuricemia mouse model at a dose of 10 mg/kg compared to isobavachin and lesinurad. Overall, our results suggest that compound 27b represents a novel, safe hURAT1 and GLUT9 dual-target inhibitor with excellent drug availability and is worthy of further investigation as an anti-hyperuricemia agent.

01 Jun 2024·Bioorganic chemistry

Discovery of digallic acid as XOD/URAT1 dual target inhibitor for the treatment of hyperuricemia

Article

Author: Zhao, Zean ; Zheng, Fengxin ; Zhang, Qun ; Mai, Suiqing ; Pang, Jianxin ; Wu, Ting ; Lin, Shiqin ; Guo, Zitao ; Ke, Jiale ; Liao, Hui ; Zhao, Pei ; Ye, Wenjie ; Zhang, Shuqin ; Hu, Huazhong ; Cen, Xiaolin ; Tian, Yuanxin

The development of XOD/URAT1 dual target inhibitors has emerged as a promising therapeutic strategy for the management of hyperuricemia. Here, through virtual screening, we have identified digallic acid as a novel dual target inhibitor of XOD/URAT1 and subsequently evaluated its pharmacological properties, pharmacokinetics, and toxicities. Digallic acid inhibited URAT1 with an IC₅₀ of 5.34 ± 0.65 μM, which is less potent than benzbromarone (2.01 ± 0.36 μM) but more potent than lesinurad (10.36 ± 1.23 μM). Docking and mutation analysis indicated that residues S35, F241 and R477 of URAT1 confer a high affinity for digallic acid. Digallic acid inhibited XOD with an IC₅₀ of 1.04 ± 0.23 μM. Its metabolic product, gallic acid, inhibited XOD with an IC₅₀ of 0.91 ± 0.14 μM. Enzyme kinetic studies indicated that both digallic acid and gallic acid act as mixed-type XOD inhibitors. It shares the same binding mode as digallic acid, and residues E802, R880, F914, T1010, N768 and F1009 contribute to their high affinity. The anion group (carboxyl) of digallic acid contribute significantly to its inhibition activity on both XOD and URAT1 as indicated by docking analysis. Remarkably, at a dosage of 10 mg/kg in vivo, digallic acid exhibited a stronger urate-lowering and uricosuric effect compared to the positive drug benzbromarone and lesinurad. Pharmacokinetic study indicated that digallic acid can be hydrolyzed into gallic acid in vivo and has a t_1/2 of 0.77 ± 0.10 h. Further toxicity evaluation indicated that digallic acid exhibited no obvious renal toxicity, as reflected by CCK-8, biochemical analysis (CR and BUN) and HE examination. The findings of our study can provide valuable insights for the development of XOD/URAT1 dual target inhibitors, and digallic acid deserves further investigation as a potential anti-hyperuricemic drug.

01 Apr 2024·European journal of medicinal chemistry

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities

Article

Author: Zheng, Fengxin ; Luo, Lijun ; Zhao, Kunlu ; Sheng, Li ; Zhai, Jiayu ; Pang, Jianxin ; Liao, Hui ; Wu, Ting ; Li, Gang ; Huan, Yi ; Meng, Bingxu ; Huang, Haihong ; Zhao, Hongyi ; Tian, Jinhong ; Li, Shengnan ; Lei, Lei

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC₅₀ values ranging from 0.052 to 0.56 μM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K⁺ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

1

News (Medical) associated with Lesinurad

12 Jun 2024

·www.globenewswire.com

Connect Biopharma Announces New Leadership and Chair of the Board of Directors

Industry leader Barry Quart, Pharm.D. appointed as Chief Executive Officer succeeding Zheng Wei, Ph.D., who will remain on the Board of Directors and serve as an advisor to assist with the transitionExperienced life science executive David Szekeres appointed as PresidentKleanthis G. Xanthopoulos, Ph.D. appointed as Chair of the Board of Directors SAN DIEGO, CA and TAICANG, China, June 12, 2024 (GLOBE NEWSWIRE) -- Connect Biopharma Holdings Limited (Nasdaq: CNTB) (Connect or the Company), a U.S.-headquartered, global clinical-stage biopharmaceutical company dedicated to improving the lives of patients with chronic inflammatory diseases through the development of therapies derived from T cell-driven research, announced today the appointments of Barry Quart, Pharm.D., as Chief Executive Officer (CEO) and Director, David Szekeres as President, and Kleanthis G. Xanthopoulos, Ph.D., as the new Chair of the Board of Directors (Board). Dr. Xanthopoulos, currently the lead independent member of the Board since 2022, has been appointed Chair of the Board. Dr. Xanthopoulos succeeds Wubin (Bill) Pan, Ph.D., M.B.A., who will remain on the Board and serve as an advisor to the Company during the transition. “On behalf of the board and the Connect team I would like to thank Drs. Zheng Wei and Wubin (Bill) Pan, who co-founded Connect with the vision to bring next-generation therapeutics to patients with inflammatory diseases and improve their lives. We are grateful for their contributions and unwavering commitment to the Connect mission by building an outstanding organization with Phase 3-ready programs and a robust pipeline,” said Kleanthis G. Xanthopoulos, Ph.D., Chair of the Board of Directors of Connect. “The highly differentiated data generated from positive readouts in both asthma and atopic dermatitis for the lead asset, rademikibart, establishes Connect now as a U.S.-driven late-stage company entering its pre-commercial phase. I am thrilled to welcome the new leadership team with such an impressive track record and eager to leverage Barry’s and David’s operational expertise and wealth of experience to unlock the maximum potential/value of rademikibart and the rest of the pipeline.” "Founding and leading Connect with Bill and working with many talented colleagues who are passionate about discovery and development of life-changing medicines in the past 12 years has been a true honor and privilege," said Dr. Zheng Wei. "As Connect evolved to focus on advancing rademikibart, Bill and I look forward to supporting Barry and David as Connect enters an exciting new phase." Dr. Barry Quart, the Company’s newly appointed CEO, brings over 30 years of extensive experience serving in leadership positions in biotechnology and pharmaceutical companies and developing innovative pharmaceutical products. He has personally led several early-stage biotech companies through late-stage clinical development and regulatory strategy, highlighted by nine U.S. Food and Drug Administration (FDA) approved drugs. “I am honored to assume the CEO role for Connect and to join the Board. I am incredibly excited about the potential of the Company going forward with rademikibart, which I believe to be a best-in-class competitor to dupilumab,” said Barry Quart, Pharm.D., CEO and Director of Connect. “With the multiple innovative therapies in our pipeline, a cash runway into at least 2026, and an expanded management team with proven experience in the U.S., I believe we have all the elements in place to achieve significant shareholder returns in the future.” Dr. Quart was most recently CEO at Heron Therapeutics. He first served as CEO and Director starting in 2012, transitioned to President and CEO in 2019 and was named Chair of the Board in October 2020. At Heron, Dr. Quart oversaw the development and approval of four drugs: two drugs for CINV (CINVANTI® and SUSTOL®) and two acute care drugs (ZYNRELEF® and APONVIE®). Prior to Heron, Dr. Quart co-founded Ardea Biosciences, Inc. in 2006 and served as its President and Chief Executive Officer and Director from its inception through its acquisition by AstraZeneca PLC in 2012. At Ardea, Dr. Quart invented and oversaw the development of a drug for gout (ZURAMPIC®), as well as the design and development of a series of MEK inhibitors for cancer that were licensed to Bayer AG. Dr. Quart currently serves on the Board of Directors of Kiniksa Pharmaceuticals. He is an inventor on 18 U.S. patents and an author on 75 publications and abstracts. Dr. Quart received his Pharm.D. from the University of California, San Francisco. David Szekeres is an experienced life science executive with a proven track record of creating value with deep operational, commercial, corporate development/strategy, and legal expertise. Mr. Szekeres was most recently Executive Vice President and Chief Operating Officer of Heron Therapeutics. Prior to Heron, he was the Chief Business Officer and General Counsel of Regulus Therapeutics, a clinical-stage biotech company focused on RNA therapeutics and the Head of Mergers & Acquisitions at Life Technologies Corporation. Mr. Szekeres also holds positions as the Chair of the Board of GRI Bio, Inc. (Nasdaq: GRI) and is a member of the Board of Directors of CureMatch, Colossal Biosciences, and the Sanford Burnham Prebys Medical Discovery Institute. He received his J.D. from Duke University School of Law and earned his B.A. at the University of California, Irvine. About Connect Biopharma Holdings Limited Connect Biopharma is a global, clinical-stage biopharmaceutical company applying its expertise in T cell biology and deep knowledge of the drug discovery industry to develop innovative therapies to treat chronic inflammatory diseases with the goal of improving the lives of millions of those affected around the world. The Company is building a rich pipeline of proprietary small molecules and antibodies, using functional T cell assays, to screen and discover potent product candidates against validated immune targets. The Company’s lead product candidate, rademikibart (formerly known as CBP-201), is an antibody designed to target interleukin-4 receptor alpha (IL-4Rα) in development for the treatment of atopic dermatitis and asthma. The Company’s second product candidate, icanbelimod (formerly known as CBP-307), is a modulator of S1P1 T cell receptors and is in development for the treatment of ulcerative colitis (UC). For more information, please visit: https://www.connectbiopharm.com/ Forward-Looking Statements Connect Biopharma cautions that statements included in this press release that are not a description of historical facts are forward-looking statements. Words such as “may”, “could”, “will”, “would”, “should”, “expect”, “plan”, “anticipate”, “believe”, “estimate”, “intend”, “predict”, “seek”, “contemplate”, “look forward”, “potential”, “continue” or “project” or the negative of these terms or other comparable terminology are intended to identify forward-looking statements. These statements include the Company’s plans to advance the development of its product candidates, the timing of achieving any development, regulatory or commercial milestones or reporting data or whether such milestones or data will be achieved or generated, including whether any new drug application will be submitted or accepted and the timing thereof, and the potential of such product candidates, including to achieve any benefit, improvement, differentiation, trend or profile or any product approval or be effective, and the sufficiency of the Company’s cash and investments to support planned operations. The inclusion of forward-looking statements should not be regarded as a representation by Connect Biopharma that any of its plans will be achieved. Actual data may differ materially from those set forth in this release due to the risks and uncertainties inherent in the Company’s business and other risks described in the Company’s filings with the Securities and Exchange Commission (SEC), including the Company’s Annual Report on Form 20-F filed with the SEC on April 16, 2024, and its other reports. Investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Connect Biopharma undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. Further information regarding these and other risks is included in Connect Biopharma’s filings with the SEC which are available from the SEC’s website (www.sec.gov) and on Connect Biopharma’s website (www.connectbiopharm.com) under the heading “Investors.” All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995. INVESTOR CONTACT:Tim McCarthyLifeSci Advisorstim@lifesciadvisors.com

Executive ChangeAcquisition

100 Deals associated with Lesinurad

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External Link

KEGG	Wiki	ATC	Drug Bank
D09921	Lesinurad	M04AB05	DB11560

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Gout	US	Ironwood Pharmaceuticals, Inc.	22 Dec 2015
Hyperuricemia	US	Ironwood Pharmaceuticals, Inc.	22 Dec 2015

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic tophaceous gout	Phase 3	US	Ardea Biosciences, Inc.	01 Jan 2012
Chronic tophaceous gout	Phase 3	AU	Ardea Biosciences, Inc.	01 Jan 2012
Chronic tophaceous gout	Phase 3	CA	Ardea Biosciences, Inc.	01 Jan 2012
Chronic tophaceous gout	Phase 3	NZ	Ardea Biosciences, Inc.	01 Jan 2012
Chronic tophaceous gout	Phase 3	PL	Ardea Biosciences, Inc.	01 Jan 2012
Chronic tophaceous gout	Phase 3	CH	Ardea Biosciences, Inc.	01 Jan 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03226899 (CTgov)	Phase 4	Gout \| Chronic Kidney Diseases	242	Placebo+XOI+colchicine (Placebo + XOI)	qqwrpfhkiv(lwbjrpjwyj) = uneiflrjbu ejnizwlhlq (qzulhsaqce, izfomujpoe - azcbmuetcf) View more	-	04 Nov 2021
				corticosteroids+Lesinurad+XOI+colchicine (Lesinurad + XOI)	qqwrpfhkiv(lwbjrpjwyj) = thmwhqzcis ejnizwlhlq (qzulhsaqce, sugqtwhvdi - zkdwbxgwwi) View more
NCT01510769 (CRYSTAL extension, Pubmed \| Arthritis Res Ther)	Phase 3	Chronic tophaceous gout	235	Lesinurad plus Febuxostat	nytryzwxqc(sxypjbeehi) = cjhvkfpsly lklcbdpogs (jilytafsrg )	-	07 Jan 2019
NCT01808144 (CRYSTAL, CTgov)	Phase 3	Gout	196	lesinurad+febuxostat (Lesinurad 400 mg + Febuxostat 80 mg)	segcgzdzjy(ihfdahoopl) = dxkuypkqom ebtvdmahxp (ojvibufvuz, eprrymuird - glfzwqobpu) View more	-	30 Jan 2018
				lesinurad+febuxostat (Lesinurad 200 mg + Febuxostat 80 mg)	segcgzdzjy(ihfdahoopl) = rdskkfxeif ebtvdmahxp (ojvibufvuz, gmtfcyzrve - ebhlbjjsxu) View more
NCT01508702 (Pubmed \| Rheumatology (Oxford)) Manual	Phase 3	Gout	214	Lesinurad	dooxreqpcb(kvwnayvhgn) = vfeogycxle kbtpbjtird (jiipskaofb ) View more	Positive	01 Dec 2017
				Placebo	dooxreqpcb(kvwnayvhgn) = khqnbxitcu kbtpbjtird (jiipskaofb ) View more
NCT01510769 (Pubmed \| Arthritis Rheumatol)	Phase 3	Chronic tophaceous gout	324	Lesinurad 200 mg	bfuqcxfkkj(ygqjevbmdw) = ewtcipsyyf wilyigztbi (yfibfonevo ) View more	Positive	01 Sep 2017
				Lesinurad 400 mg	bfuqcxfkkj(ygqjevbmdw) = cttkpmmzhm wilyigztbi (yfibfonevo ) View more
NCT01493531 (CLEAR 2, Pubmed \| Ann Rheum Dis)	Phase 3	Gout serum uric acid (sUA)	610	Lesinurad 200 mg + Allopurinol	bwyufagqfp(nwldegpskl) = hjpmwbmdbv oihhgstmxa (jvayywnylg )	-	01 May 2017
				Lesinurad 400 mg + Allopurinol	bwyufagqfp(nwldegpskl) = qgsdeeqxdy oihhgstmxa (jvayywnylg )
NCT01808131 (CLEAR 1 & 2, ACR2016)	Phase 3	Gout serum uric acid (sUA)	-	Lesinurad 200 mg + Allopurinol	nlysmurlmq(lgnworzesz) = EAIRs of kidney stone TEAEs were 0.5 and 2.0 for LESU200 and LESU400, respectively wzkisamxog (zszcjlidhf ) View more	Positive	13 Nov 2016
				Lesinurad 400 mg + Allopurinol
NCT01510158 (CLEAR 1, CTgov)	Phase 3	Gout	607	Lesinurad+Allopurinol (Lesinurad 200 mg + Allopurinol)	awainiiwpy(kzyomqqjqm) = xwccfnxzop oatqwatwgp (yekybefvpm, ibevuijdga - wzzpgrxlvg) View more	-	18 Aug 2016
				Lesinurad+Allopurinol (Lesinurad 400 mg + Allopurinol)	awainiiwpy(kzyomqqjqm) = elothzlbed oatqwatwgp (yekybefvpm, lrcjetakbw - kbhfidhapm) View more
EULAR2016	Phase 3	Gout	-	Lesinurad 200 mg + Allopurinol	azodsaqwvw(fblxzgiqqx) = tsgjqzsfrc qqktnchwac (ipzunfihen )	-	08 Jun 2016
				Lesinurad 400 mg + Allopurinol	azodsaqwvw(fblxzgiqqx) = ijxsjgfyax qqktnchwac (ipzunfihen )
NCT01808131 (CLEAR 1 and 2, EULAR2016)	Phase 3	Gout serum uric acid (SUA)	-	Lesinurad 200 mg + Allopurinol	vqtpfghciu(dlzpdbtjve) = EAIRs (per 100-PY) of TEAEs and serious TEAEs at any time during core or extension studies were 54.2 and 5.8 for LESU200 and 57.2 and 8.3 for LESU400. zwsgarjxgq (wmduzxvptv ) View more	Positive	08 Jun 2016
				Lesinurad 400 mg + Allopurinol