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.
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| 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
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:
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| 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
