Zomepirac

Zomepirac
Clinical data
Routes of; administration	By mouth
ATC code	M01AB04 (WHO) ;
Legal status
Legal status	withdrawn;
Identifiers
	IUPAC name 2-[5-(4-Chlorobenzoyl)-1,4-dimethyl-pyrrol-2-yl]acetic acid;
CAS Number	33369-31-2 ;
PubChem CID	5733;
DrugBank	DB04828 ;
ChemSpider	5531 ;
UNII	822G987U9J;
ChEBI	CHEBI:35859 ;
ChEMBL	ChEMBL19490 ;
CompTox Dashboard (EPA)	DTXSID9023754 ;
ECHA InfoCard	100.046.780
Chemical and physical data
Formula	C15H14ClNO3
Molar mass	291.73 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(c1c(cc(n1C)CC(=O)O)C)c2ccc(Cl)cc2;
	InChI 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) ; Key:ZXVNMYWKKDOREA-UHFFFAOYSA-N ;
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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by doctors in many situations and obtained a large share of the analgesics market; however, it was subsequently withdrawn in March 1983 due to its tendency to cause serious anaphylaxis in a small, but unpredictable, subset of the patient population.^[1]^[2]

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 The chemical structure differs from other NSAIDs in that the central benzene ring has been replaced by a pyrrole.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).

References

^ Rheinstein PH (September 1992). "Reporting of adverse drug events: a key to postmarketing drug safety". American Family Physician. 46 (3): 873–874. PMID 1514478.
^ Grillo MP, Hua F (November 2003). "Identification of zomepirac-S-acyl-glutathione in vitro in incubations with rat hepatocytes and in vivo in rat bile". Drug Metabolism and Disposition. 31 (11): 1429–1436. doi:10.1124/dmd.31.11.1429. PMID 14570776. S2CID 9912756.
^ ^a ^b Lewis JR (1981). "Zomepirac sodium. A new nonaddicting analgesic". JAMA. 246 (4): 377–379. doi:10.1001/jama.246.4.377. PMID 7241789.
^ 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): 382–391. doi:10.1185/03007998309111743. PMID 6221886.
^ Mehlisch DR, Joy ED (June 1981). "Zomepirac sodium vs APC with codeine for oral surgery pain". Journal of Oral Surgery. 39 (6): 426–429. PMID 7014804.
^ Stambaugh JE, Sarajian C (1981). "Analgesic efficacy of zomepirac sodium in patients with pain due to cancer". Journal of Clinical Pharmacology. 21 (11): 501–507. doi:10.1002/j.1552-4604.1981.tb05657.x. PMID 7037868. S2CID 19347859.
^ Evans PJ, McQuay HJ, Rolfe M, O'Sullivan G, Bullingham RE, Moore RA (September 1982). "Zomepirac, placebo and paracetamol/dextropropoxyphene combination compared in orthopaedic postoperative pain". British Journal of Anaesthesia. 54 (9): 927–933. doi:10.1093/bja/54.9.927. PMID 7052110.
^ Baird WM, Turek D (April 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): 243–249. doi:10.1002/j.1552-4604.1980.tb01704.x. PMID 6991540. S2CID 7637029.
^ Mehlisch DR, Joy ED, Moore TE, Porter K, Stumpf AJ, Wolfe SH (April 1980). "Clinical comparison of zomepirac with APC/codeine combination in the treatment of pain following oral surgery". Journal of Clinical Pharmacology. 20 (4): 271–278. doi:10.1002/j.1552-4604.1980.tb01708.x. PMID 6991544. S2CID 45366160.
^ Diamond S, Medina JL (March 1981). "A double-blind study of zomepirac sodium and placebo in the treatment of muscle contraction headache". Headache. 21 (2): 45–48. doi:10.1111/j.1526-4610.1981.hed2102045.x. PMID 7016809. S2CID 41806718.
^ Wallenstein SL, Rogers A, Kaiko RF, Heidrich G, Houde RW (April 1980). "Relative analgesic potency of oral zomepirac and intramuscular morphine in cancer patients with postoperative pain". Journal of Clinical Pharmacology. 20 (4): 250–258. doi:10.1002/j.1552-4604.1980.tb01705.x. PMID 6991541. S2CID 11808742.
^ 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.
^ Smith PC, McDonagh AF, Benet LZ (March 1986). "Irreversible binding of zomepirac to plasma protein in vitro and in vivo". The Journal of Clinical Investigation. 77 (3): 934–939. doi:10.1172/JCI112392. PMC 423485. PMID 3949982.
^ Carson JR, Wong S (February 1973). "5-Benzoyl-1-methylpyrrole-2-acetic acids as antiinflammatory agents. 2. The 4-methyl compounds". Journal of Medicinal Chemistry. 16 (2): 172–174. doi:10.1021/jm00260a023. PMID 4683116.
^ DE 2102746, Carson JR, "5-Aroylpyrrole [5-aroyl pyrroles]", published 1971-08-12, assigned to McNeil Laboratories Inc.
^ US 3752826, Carson JS, issued 1973, assigned to McNeil

[1] Rheinstein PH (September 1992). "Reporting of adverse drug events: a key to postmarketing drug safety". American Family Physician. 46 (3): 873–874. PMID 1514478.

[2] Grillo MP, Hua F (November 2003). "Identification of zomepirac-S-acyl-glutathione in vitro in incubations with rat hepatocytes and in vivo in rat bile". Drug Metabolism and Disposition. 31 (11): 1429–1436. doi:10.1124/dmd.31.11.1429. PMID 14570776. S2CID 9912756.

[JAMA-3] Lewis JR (1981). "Zomepirac sodium. A new nonaddicting analgesic". JAMA. 246 (4): 377–379. 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): 382–391. doi:10.1185/03007998309111743. PMID 6221886.

[5] Mehlisch DR, Joy ED (June 1981). "Zomepirac sodium vs APC with codeine for oral surgery pain". Journal of Oral Surgery. 39 (6): 426–429. 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): 501–507. 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 (September 1982). "Zomepirac, placebo and paracetamol/dextropropoxyphene combination compared in orthopaedic postoperative pain". British Journal of Anaesthesia. 54 (9): 927–933. doi:10.1093/bja/54.9.927. PMID 7052110.

[8] Baird WM, Turek D (April 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): 243–249. 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 (April 1980). "Clinical comparison of zomepirac with APC/codeine combination in the treatment of pain following oral surgery". Journal of Clinical Pharmacology. 20 (4): 271–278. doi:10.1002/j.1552-4604.1980.tb01708.x. PMID 6991544. S2CID 45366160.

[10] Diamond S, Medina JL (March 1981). "A double-blind study of zomepirac sodium and placebo in the treatment of muscle contraction headache". Headache. 21 (2): 45–48. doi:10.1111/j.1526-4610.1981.hed2102045.x. PMID 7016809. S2CID 41806718.

[11] Wallenstein SL, Rogers A, Kaiko RF, Heidrich G, Houde RW (April 1980). "Relative analgesic potency of oral zomepirac and intramuscular morphine in cancer patients with postoperative pain". Journal of Clinical Pharmacology. 20 (4): 250–258. 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.

[Smith1986-13] Smith PC, McDonagh AF, Benet LZ (March 1986). "Irreversible binding of zomepirac to plasma protein in vitro and in vivo". The Journal of Clinical Investigation. 77 (3): 934–939. doi:10.1172/JCI112392. PMC 423485. PMID 3949982.

[14] Carson JR, Wong S (February 1973). "5-Benzoyl-1-methylpyrrole-2-acetic acids as antiinflammatory agents. 2. The 4-methyl compounds". Journal of Medicinal Chemistry. 16 (2): 172–174. doi:10.1021/jm00260a023. PMID 4683116.

[15] DE 2102746, Carson JR, "5-Aroylpyrrole [5-aroyl pyrroles]", published 1971-08-12, assigned to McNeil Laboratories Inc.

[16] US 3752826, Carson JS, issued 1973, assigned to McNeil

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