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Sulindac

From Wikipedia, the free encyclopedia
Nonsteroidal anti-inflammatory drug (NSAID)
Pharmaceutical compound
Sulindac
Clinical data
Trade namesClinoril
AHFS/Drugs.comMonograph
MedlinePlusa681037
Pregnancy
category
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityApproximately 90% (Oral)
Metabolism?
Eliminationhalf-life7.8 hours, metabolites up to 16.4 hours
ExcretionRenal (50%) and fecal (25%)
Identifiers
  • {(1Z)-5-fluoro-2-methyl-1-[4-(methylsulfinyl)benzylidene]-1H-indene-3-yl}acetic acid
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.048.909Edit this at Wikidata
Chemical and physical data
FormulaC20H17FO3S
Molar mass356.41 g·mol−1
3D model (JSmol)
Melting point182 to 185 °C (360 to 365 °F) (decomp.)
  • O=S(c1ccc(cc1)\C=C3/c2ccc(F)cc2\C(=C3C)CC(=O)O)C
  • InChI=1S/C20H17FO3S/c1-12-17(9-13-3-6-15(7-4-13)25(2)24)16-8-5-14(21)10-19(16)18(12)11-20(22)23/h3-10H,11H2,1-2H3,(H,22,23)/b17-9- checkY
  • Key:MLKXDPUZXIRXEP-MFOYZWKCSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Sulindac is anonsteroidal anti-inflammatory drug (NSAID) of the arylalkanoic acid class that is marketed asClinoril. Imbaral (not to be confused withmebaral) is another name for this drug. Its name is derived from sul(finyl)+ ind(ene)+ ac(etic acid)It was patented in 1969 and approved for medical use in 1976.[1]

Medical uses

[edit]

Like other NSAIDs, it is useful in the treatment ofacute orchronicinflammatory conditions. Sulindac is aprodrug, derived fromsulfinylindene, that is converted in the body to the active NSAID. More specifically, the agent is converted by liver enzymes to a sulfide that is excreted in the bile and then reabsorbed from the intestine. This is thought to help maintain constant blood levels with reduced gastrointestinal side effects. Some studies have shown sulindac to be relatively less irritating to the stomach than other NSAIDs except for drugs of theCOX-2 inhibitor class.[2] The exact mechanism of its NSAID properties is unknown, but it is thought to act on enzymes COX-1 and COX-2, inhibitingprostaglandin synthesis.

Its usualdosage is 150-200milligrams twice per day, with food. It should not be used by persons with a history of major allergic reactions (urticaria oranaphylaxis) toaspirin or other NSAIDs, and should be used with caution by persons having pre-existingpeptic ulcer disease. Sulindac is much more likely than other NSAIDs to cause damage to the liver or pancreas, though it is less likely to cause kidney damage than other NSAIDs.

Sulindac seems to have a property, independent of COX-inhibition, of reducing the growth of polyps and precancerous lesions in the colon, especially in association withfamilial adenomatous polyposis, and may have other anti-cancer properties.[3][4]

Adverse effects

[edit]

In October 2020, the U.S.Food and Drug Administration (FDA) required thedrug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.[5][6] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[5][6]

Society and culture

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Litigation

[edit]

In September 2010 a federal jury in New Hampshire awarded $21 million to Karen Bartlett, a woman who developedStevens–Johnson syndrome/Toxic epidermal necrolysis as a result of taking a generic brand of sulindac manufactured by Mutual Pharmaceuticals for her shoulder pain. Ms. Bartlett sustained severe injuries including the loss of over 60% of her surface skin and permanent near-blindness. The case had been appealed to the United States Supreme Court, where the main issue was whether federal law preempts Ms. Bartlett's claim.[7] On June 24, 2013, the Supreme Court ruled 5–4 in favor of Mutual Pharmaceuticals, throwing out the earlier $21 million jury verdict.[8][9]

Synthesis

[edit]
Sulindac synthesis:[10][11][12][13]

Rxn ofp-fluorobenzyl chloride (1) with the anion of diethylmethyl malonate (2) gives intermediate diester (3), saponification of which and subsequent decarboxylation leads to4. {Alternatively it can be formed byPerkin reaction between p-fluorobenzaldehyde andpropionic anhydride in the presence ofNaOAc, followed bycatalytic hydrogenation of the olefinic bond using a palladium on carbon catalyst.}

Polyphosphoric acid (PPA) cyclization leads to 5-fluoro-2-methyl-3-indanone (4). AReformatsky reaction withzincamalgam and bromoacetic ester leads to carbinol (5), which is then dehydrated withtosic acid to indene6. {Alternatively, this step can be performed in aKnoevenagel condensation withcyanoacetic acid, which is then further decarboxylated.}

The active methylene group is condensed withp-methylthiobenzaldehyde, usingsodium methoxide as catalyst, and then saponified to giveZ (7) which in turn oxidized withsodium metaperiodate to sulfoxide8, theantiinflammatory agent sulindac.

References

[edit]
  1. ^Fischer J, Ganellin CR (2006).Analogue-based Drug Discovery. John Wiley & Sons. p. 517.ISBN 9783527607495.
  2. ^"Sulindac".LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. 2012.PMID 31643638.
  3. ^Scheper MA, Nikitakis NG, Chaisuparat R, Montaner S, Sauk JJ (March 2007)."Sulindac induces apoptosis and inhibits tumor growth in vivo in head and neck squamous cell carcinoma".Neoplasia.9 (3):192–199.doi:10.1593/neo.06781.PMC 1838577.PMID 17401459. Archived fromthe original on 2012-09-05.
  4. ^Shiff SJ, Qiao L, Tsai LL, Rigas B (July 1995)."Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells".The Journal of Clinical Investigation.96 (1):491–503.doi:10.1172/JCI118060.PMC 185223.PMID 7615821.
  5. ^ab"FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications".U.S.Food and Drug Administration (FDA) (Press release). 15 October 2020. Retrieved15 October 2020.Public Domain This article incorporates text from this source, which is in thepublic domain.
  6. ^ab"NSAIDs may cause rare kidney problems in unborn babies".U.S. Food and Drug Administration. 21 July 2017. Retrieved15 October 2020.Public Domain This article incorporates text from this source, which is in thepublic domain.
  7. ^Thomas K (2013-03-04)."Justices to Take Up Case on Generic Drug Markers' Liability".New York Times. Retrieved4 March 2013.
  8. ^Kendall B."Supreme Court Again Limits Product-Liability Suits on Generic Drugs". Wall Street Journal. Retrieved24 June 2013.
  9. ^Bartlett v. Mut. Pharm. Co., Inc., 678 F.3d 30 (D.C. Cir. March 19, 2013).
  10. ^Shuman RF, Pines SH, Shearin WE, Czaja RF, Abramson NL, Tull R (1977). "A sterically efficient synthesis of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid and its S-oxide, sulindac".The Journal of Organic Chemistry.42 (11):1914–1919.doi:10.1021/jo00431a019.
  11. ^DE 2039426, Greenwald RB, Witzel EB, "Indenyl acetic acid and process for its preparation", issued 20 February 1975, assigned to Merck and Co Inc. 
  12. ^US 3647858, Conn JB, Hinkley DF, "Process for preparing 1-benzylidene-3-indenyl acetic acids", issued 7 March 1972, assigned to Merck and Co Inc. 
  13. ^US 3654349, Greenwald RB, Jones H, "Substituted indenyl acetic acids", issued 4 April 1972, assigned to Merck and Co Inc. 

External links

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pyrazolones /
pyrazolidines
salicylates
acetic acid derivatives
and related substances
oxicams
propionic acid
derivatives (profens)
n-arylanthranilic
acids (fenamates)
COX-2 inhibitors
(coxibs)
other
NSAID
combinations
Key:underline indicates initially developed first-in-class compound of specific group;#WHO-Essential Medicines;withdrawn drugs;veterinary use.
Receptor
(ligands)
DP (D2)Tooltip Prostaglandin D2 receptor
DP1Tooltip Prostaglandin D2 receptor 1
DP2Tooltip Prostaglandin D2 receptor 2
EP (E2)Tooltip Prostaglandin E2 receptor
EP1Tooltip Prostaglandin EP1 receptor
EP2Tooltip Prostaglandin EP2 receptor
EP3Tooltip Prostaglandin EP3 receptor
EP4Tooltip Prostaglandin EP4 receptor
Unsorted
FP (F)Tooltip Prostaglandin F receptor
IP (I2)Tooltip Prostacyclin receptor
TP (TXA2)Tooltip Thromboxane receptor
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Enzyme
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PTGS)
PGD2STooltip Prostaglandin D synthase
PGESTooltip Prostaglandin E synthase
PGFSTooltip Prostaglandin F synthase
PGI2STooltip Prostacyclin synthase
TXASTooltip Thromboxane A synthase
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