Zomepirac

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Zomepirac
Zomepirac.svg
Clinical data
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • withdrawn
Identifiers
  • 2-[5-(4-Chlorobenzoyl)-1,4-dimethyl-pyrrol-2-yl]acetic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.046.780 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H14ClNO3
Molar mass 291.73 g·mol−1
3D model (JSmol)
  • O=C(c1c(cc(n1C)CC(=O)O)C)c2ccc(Cl)cc2
  • InChI=1S/C15H14ClNO3/c1-9-7-12(8-13(18)19)17(2)14(9)15(20)10-3-5-11(16)6-4-10/h3-7H,8H2,1-2H3,(H,18,19) Yes check.svgY
  • Key:ZXVNMYWKKDOREA-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Zomepirac is an orally effective nonsteroidal anti-inflammatory drug (NSAID) that has antipyretic actions. It was developed by McNeil Pharmaceutical, approved by the FDA in 1980, and sold as the sodium salt zomepirac sodium, under the brand name Zomax. Due to its clinical effectiveness, it was preferred by doctors in many situations and obtained a large share of the analgesics market; however, it was subsequently withdrawn in March 1983 due to its tendency to cause serious anaphylaxis in a small, but unpredictable, subset of the patient population. [1] [2]

Contents

Indications

Zomepirac was indicated for the management of mild to severe pain. [3] Multiple clinical trials demonstrated zomepirac to be more effective than aspirin or codeine alone and to be as effective as analgesic combinations containing codeine or other opioids. [4] [5] [6] [7] [8] [9] [10] Zomepirac provided analgesia comparable with usual intramuscular doses of morphine in postoperative pain and that with long-term use, neither tolerance to its analgesic effect nor psychological or physical dependence had been demonstrated. [3] [11]

Chemical structure

Zomepirac is the sodium salt of 5-(4-chlorobenzoyl)-1,4 dimethyl-1H-pyrrole-2-acetate dihydrate. It is a pyrrole-acetic acid which is structurally related to tolmetin. The chemical structure differs from other NSAIDs in that the central benzene ring has been replaced by a pyrrole.

Mechanism of action

Zomepirac is a prostaglandin synthetase inhibitor. [12]

Anaphylaxis

Zomepirac does not cause anaphylaxis directly, but it is metabolized by UDP-glucuronosyltransferase (UGT) to a reactive glucuronide which binds irreversibly to plasma albumin. [13]

Synthesis

Zomepirac can be synthesized from diethyl 1,3-acetonedicarboxylate, chloroacetone, and aqueous methylamine (MeNH2) via modification of the Hantzsch pyrrole synthesis to give intermediate 1. Saponification, monoesterification, and thermal decarboxylation gives ester 2. This is acylated with N,N-dimethyl-p-chlorobenzamide, and finally saponification gives zomepirac (3).

Zomepirac synthesis: Zomepirac synthesis.svg
Zomepirac synthesis:

See also

Related Research Articles

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References

  1. Peter H. Rheinstein (September 1992). "Reporting of adverse drug events: a key to postmarketing drug safety". American Family Physician.
  2. Mark P. Grillo and Fengmei Hua (August 19, 2003). "Identification of Zomepirac-S-Acyl-Glutathione in In Vitro Incubations with Rat Hepatocyles and In Vitro Rate Bile". Drug Metabolism and Disposition. 31 (11): 1429–1436. doi:10.1124/dmd.31.11.1429. PMID   14570776. S2CID   9912756.
  3. 1 2 Lewis JR (1981). "Zomepirac sodium. A new nonaddicting analgesic". JAMA. 246 (4): 377–9. doi:10.1001/jama.246.4.377. PMID   7241789.
  4. Steele CE, Jefferson WL (1983). "A multi-centre study of zomepirac in painful conditions: an analysis of clinical data for 15,484 patients". Current Medical Research and Opinion. 8 (6): 382–91. doi:10.1185/03007998309111743. PMID   6221886.
  5. Mehlisch DR, Joy ED (1981). "Zomepirac sodium vs APC with codeine for oral surgery pain". Journal of Oral Surgery. 39 (6): 426–9. PMID   7014804.
  6. Stambaugh JE, Sarajian C (1981). "Analgesic efficacy of zomepirac sodium in patients with pain due to cancer". Journal of Clinical Pharmacology. 21 (11–12 Pt 1): 501–7. doi:10.1002/j.1552-4604.1981.tb05657.x. PMID   7037868. S2CID   19347859.
  7. Evans PJ, McQuay HJ, Rolfe M, O'Sullivan G, Bullingham RE, Moore RA (1982). "Zomepirac, placebo and paracetamol/dextropropoxyphene combination compared in orthopaedic postoperative pain". British Journal of Anaesthesia. 54 (9): 927–33. doi: 10.1093/bja/54.9.927 . PMID   7052110.
  8. Baird WM, Turek D (1980). "Comparison of zomepirac, APC with codeine, codeine and placebo in the treatment of moderate and severe postoperative pain". Journal of Clinical Pharmacology. 20 (4 Pt 2): 243–9. doi:10.1002/j.1552-4604.1980.tb01704.x. PMID   6991540. S2CID   7637029.
  9. Mehlisch DR, Joy ED, Moore TE, Porter K, Stumpf AJ, Wolfe SH (1980). "Clinical comparison of zomepirac with APC/codeine combination in the treatment of pain following oral surgery". Journal of Clinical Pharmacology. 20 (4 Pt 2): 271–8. doi:10.1002/j.1552-4604.1980.tb01708.x. PMID   6991544. S2CID   45366160.
  10. Diamond S, Medina JL (1981). "A double-blind study of zomepirac sodium and placebo in the treatment of muscle contraction headache". Headache. 21 (2): 45–8. doi:10.1111/j.1526-4610.1981.hed2102045.x. PMID   7016809. S2CID   41806718.
  11. Wallenstein SL, Rogers A, Kaiko RF, Heidrich G, Houde RW (1980). "Relative analgesic potency of oral zomepirac and intramuscular morphine in cancer patients with postoperative pain". Journal of Clinical Pharmacology. 20 (4 Pt 2): 250–8. doi:10.1002/j.1552-4604.1980.tb01705.x. PMID   6991541. S2CID   11808742.
  12. DC McLeod, Zomepirac (Zomax, McNeil Pharmaceutical) Archived September 28, 2007, at the Wayback Machine , Drug Intelligence & Clinical Pharmacy: Vol. 15, No. 7, pp. 522-530.
  13. Smith, P. C.; McDonagh, A. F.; Benet, L. Z. (1986). "Irreversible binding of zomepirac to plasma protein in vitro and in vivo". Journal of Clinical Investigation. 77 (3): 934–939. doi:10.1172/JCI112392. PMC   423485 . PMID   3949982.
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  15. DE 2102746,Carson, John Robert,"5-Aroylpyrrole [5-aroyl pyrroles]",published 1971-08-12, assigned to McNeil Laboratories Inc.
  16. J. R. Carson, U.S. Patent 3,752,826 (1973 to McNeil).