Tuesday, March 8, 2016

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).


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: 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.


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.


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).


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.
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