Lesinurad I Urate Transporter 1 Inhibitor | Organic Anion Transporter 4 Inhibitor | Treatment for Gout | Treatment for Hyperuricemia

Lesinurad [2-{[5-Bromo-4-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid] is an oral uricosuric agent for the treatment of hyperuricemia in patients with gout. Lesinurad is a selective uric acid reabsorption inhibitor (SURI) of urate transporter 1 (URAT1) in the proximal tubule of the kidney. It also has effects on organic anion transporter 4 (OAT4), the transporter through which the diuretics cause hyperuricemia, but has no effect on other transporters such as OAT1 and OAT3. Through this dual inhibition mechanism Lesinurad thereby normalizes uric acid excretion and reduces serum uric acid (sUA) [1].

Lesinurad was investigated as an add-on therapy to allopurinol or febuxostat (XOI, xanthine oxidase inhibitor) in phase III trials at the dose of 200 and 400mg daily, but could possibly be used in monotherapy when these drugs are contraindicated. 

The discovery of Lesinurad started with studies on RDEA806, which was a non-nucleoside reverse transcriptase inhibitor in trials for the potential treatment of HIV. Later in 2009, RDEA806 was assessed for its hypouricemic effects, where the results were much better than those for HIV studies. Lesinurad (then named as RDEA594) is the active metabolite of RDEA806.

Lesinurad: 2D and 3D Structure

URAT1 and Hyperuricemia of Gout

Gout is caused by a lack of efficient excretion of uric acid, resulting in hyperuricemia and the formation of crystal deposits of uric acid. The renal uric acid transporter URAT1 is important for regulating serum uric acid levels, and URAT1 inhibitors reduce serum uric acid levels and are used as gout therapies [2].

Lesinurad Inhibits URAT1

HEK-293T cells transiently expressing chimeric URAT1 mutants were used to measure cell-based uric acid transport activity. Lesinurad inhibits the uric acid transport activity of human URAT1 (hURAT1) at a 20-fold higher potency compared to rat URAT1 (rURAT1), with IC₅₀'s of 3.36 and 74.84 µM, respectively. 

Lesinurad inhibits hURAT1 through an interaction that involves a critical residue, Phe365. The gain-of-function phenotype of rURAT1-Phe365 suggests that Phe365 directly binds to Lesinurad. Chimeras containing portions of the rat and human genes identified a single residue, hURAT1 phe365, located within transmembrane segment 7, as crucial for the higher affinity interaction with Lesinurad. This residue is a tyrosine in rURAT1. In particular, the single chimeric point mutant hURAT1-Tyr365 shows a significantly reduced sensitivity for inhibition by lesinurad (IC₅₀ = 47.76 µM) compared to wild type hURAT1, while the converse point mutant rURAT1-Phe365 displays a significantly enhanced sensitivity (IC₅₀ = 6.82 µM) compared to wild type rURAT1 [3].

Dosages and Approval

Lesinurad (Tradename: Zurampic) was developed at Ardea Biosciences as a part of  RDEA spectrum of drugs intended to meet the unmet need of managing hyperuricemia by conventional agents. In 2012, AstraZeneca bought Ardea Biosciences influenced by the success of Lesinurad in trials and also because of more such drugs in pipeline. Lesinurad was approved by the U.S. Food and Drug Administration (FDA) on Dec 22, 2015.

The recommended starting dosage of Lesinurad is 200 mg once daily, to be taken orally in the morning along with food and water. This is also the maximum daily dose. Lesinurad should be coadministered with an XOI, including Allopurinol or Febuxostat. The drug may be added when target serum uric acid levels are not achieved on the medically appropriate dose of the XOI alone. The use of Lesinurad is not recommended in patients taking daily doses of Allopurinol of less than 300 mg (or less than 200 mg in patients with an estimated creatinine clearance of less than 60 mL/min).

Summary

Common name: RDEA594; RDEA 594; RDEA-594

Trademarks: Zurampic

Molecular Formula: C17H14BrN3O2S

CAS Registry Number: 878672-00-5; 1151516-14-1 (sodium salt)

CAS Name: 2-{[5-Bromo-4-(4-cyclopropyl-1-naphthyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid

Molecular Weight: 404.28

SMILES: c1ccc2c(c1)c(ccc2n3c(nnc3Br)SCC(=O)O)C4CC4

InChI Key: FGQFOYHRJSUHMR-UHFFFAOYSA-N

InChI: InChI=1S/C17H14BrN3O2S/c18-16-19-20-17(24-9-15(22)23)21(16)14-8-7-11(10-5-6-10)12-3-1-2-4-13(12)14/h1-4,7-8,10H,5-6,9H2,(H,22,23)

Mechanism of Action: Uric Acid Transporter 1 (URAT1) Inhibitor

Activity: Treatment of Hyperuricemia; Treatment of Gout

Status: Launched 2015 (US)

Chemical Class: Napthalene derivatives; Trizoles; Small-molecules; Bromine containing

Originator: Ardea Biosciences/AstraZeneca

Lesinurad Synthesis

WO2011085009A2: An improved route based on synthesis of RDEA806.

Intermediate:

Final Synthesis:

WO2015054960A1: It appears to be the industrial process. The yields are better here and also no thiophosgene is used in the process.

CN102040546A: Another method to prepare the thiocyanate intermediate. It is lengthy than earlier reported schemes but it is thiophosgene free.

Identifications:

1H NMR Estimated for Lesinurad

Experimental: ¹H NMR (400MHz, DMSO) δ 12.98 (s, 1H), 8.58 (d, J = 8.5Hz, 1H), 7.74 (t, J = 7.3Hz, 1H), 7.69-7.57 (m, 2H), 7.44 (d, J = 7.6Hz, 1H), 7.17 (d, J = 8.3Hz, 1H), 4.06-3.95 (m, 2H), 2.60-2.52 (m, 1H), 1.22-1.10 (m, 2H), 0.87 (q, J = 5.3Hz, 2H).

Sideffects: 

The most common adverse events reported during the treatment with Lesinurad (200 mg) in combination with an XOI were headache, flu symptoms, blood creatinine increase and gastroesophageal reflux disease (GERD). Most of which were reversible. In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, nonfatal myocardial infarctions, or nonfatal strokes) were observed with Zurampic. A causal relationship with Zurampic has not been established.

The labeling for Zurampic includes a boxed warning regarding the risk for acute renal failure, which is more common when the drug is used without an XOI or at higher-than-approved doses.

References:

1. Singh, J. A. Emerging therapies for gout. Expert Opin Emerg Drugs 2012, 17(4), 511-518.

2. Diaz-Torné, C.; et. al. New medications in development for the treatment of hyperuricemia of gout. Curr Opin Rheumatol 2015, 27(2), 164-169.
3. Tan, P. K.; et. al. Lesinurad, An Inhibitor Of The Uric Acid Transporter URAT1 and a Potential Therapy For Gout, Requires URAT1 Phenylalanine 365 For High Affinity Inhibition. [abstract]. Arthritis Rheum 2013, 65(Suppl 10), 1723. DOI: 10.1002/art.2013.65.issue-s10

Topiroxostat I Xanthine Oxidase Inhibitor I Treatment for Gout | Treatment for Hyperuricemia

Topiroxostat [4-[5-(4-Pyridinyl)-1H-1,2,4-triazol-3-yl]-2-pyridinecarbonitrile] is an oral, non-purine, selective xanthine oxidase (XO) inhibitor developed for the treatment of gout and hyperuricemia. In medicinal terminology, Topiroxostat is an antihyperuricemic agent that reduces serum uric acid level by selectively inhibiting XOR and thereby suppressing uric acid production [1].

Topiroxostat: 2D and 3D Structure

Xanthine Oxidoreductase in Uric Acid Production:

Mammalian xanthine oxidoreductase (XOR) catalyzes the last two steps in the purine degradation pathway before formation of uric acid, i.e., hydroxylation of hypoxanthine to xanthine and xanthine to uric acid. The enzyme is a homodimer with molecular mass of 290 kDa; each subunit contains one molybdenum cofactor, two [2Fe-2S] centers, and one FAD center.

The oxidative hydroxylation of purine substrates takes place at the molybdenum center, and reducing equivalents thus introduced are transferred via the two [2Fe-2S] centers to the FAD center, where reduction of the physiological electron acceptor, NAD or O₂, occurs.

Mammalian xanthine oxidoreductase (XOR) is a good target of drugs to treat gout and hyperuricemia. Allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine], a hypoxanthine isomer, was introduced as an inhibitor of XOR more than 40 years ago and has been extensively prescribed for gout and hyperuricemia patients.

Researchers have been trying to build new XOR inhibitors; and one of the success story is Febuxostat [2-(3-Cyano-4-isobutoxy-phenyl)-4-methyl-1,3-thiazole-5 carboxylic acid], which is a nonpurine selective inhibitor of XOR, and showed a more potent and longer-lasting urate-lowering effect than allopurinol in rodents. It was subsequently launched in US and EU for the treatment of gout.

Topiroxostat is developed as an unique type of XOR inhibitor. It not only forms a covalent linkage to molybdenum via oxygen in the hydroxylation reaction intermediate, but also interacts with amino acid residues of the solvent channel. For this unique exhibition of both structure- and mechanism-based inhibition, it is called termed as a hydrid-type inhibitor of XOR [1]. In addition, Topiroxostat has high bioavailability and safety in animals, hence it was short-listed as a candidate drug for hyperuricemia and gout.

Approval and Dosages:

Topiroxostat  (Tradename: Topiloric; Uriadec) was approved for use in Japan in June 2013. Fujiyakuhin Co., Ltd. and Sanwa Kagaku Kenkyusho Co., Ltd. are credited as the originators. The usual adult initial dosage is 20 mg/dose of topiroxostat orally administered twice daily in the morning and evening. Thereafter, the dose should be gradually increased, as needed, while monitoring blood uric acid levels. The usual maintenance dosage should be 60 mg/dose twice daily. The dose may be adjusted according to the patient’s condition, up to 80 mg/dose twice daily.

Topiroxostat Synthesis

WO2003064410A1: It is the oldest reported synthesis. It is considered expensive on account of TMSCN; and also N-protection/de-protection are considered as time and effort consuming.

Tetrahedron Lett 2008, 49(28), 4369-4371: It is considered as an improvement on Ref. 2. The starting material is commercially available and  Zn(CN)₂ is much cheaper than TMSCN.

Identifications:

1H NMR (Estimated) for Topiroxostat

Experimental: ¹H-NMR (DMSO-d6) δ ppm: 8.01 (2H, dd, J = 4.54 & 1.57 Hz), 8.31 (1H, dd, J = 5.11 & 1.65 Hz) , 8.53 (1H, dd, J = 1.65 & 0.50 Hz), 8.80 (2H, dd, J = 4.54 & 1.57 Hz), 8.93 (1H, dd, J = 5.11 & 0.50 Hz).

Sideeffects: The most come adverse reactions (AEs) reported are gout arthritis, cutaneous adverse events and hepatic impairment. These included gingival bleeding, oral pain, β2 microglobulin urine increase, NAG increase, blood amylase increase, eosinophilia, a1 microglobulin increase and platelet count increase. Liver disorder included ALT/AST increase, blood creatinine increase and high γ-GTP level. The patients also reported rash, cold sweat, urticaria and erythema. No bladder or kidney related AEs are reported.

References:
1. Matsumoto, K.; et. al. FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase. J Pharmacol Exp Ther 2011, 336(1), 95-103.
2. Ashizawa, N.; et. al. Novel 1,2,4-triazole compound. WO2003064410A1
3. Huo, Z.; et. al. Zinc cyanide mediated direct a-cyanation of isonicotinic acid N-oxide. Application to the synthesis of FYX-051, a xanthine oxidoreductase inhibitor. Tetrahedron Lett 2008, 49(28), 4369-4371.
4. Sato, T.; et. al. Discovery of 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051- a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia. Bioorg Med Chem Lett 2009, 19(21), 6225-6229.
5. Approval for Topiroxostat (here).