Description
Etoricoxib is a COX-2 inhibitor developed as a follow-up of rofecoxib for the treatment
of osteoarthritis, rheumatoid arthritis, dysmenorrhoea, gout, ankylosing spondylitis and
pain. Several processes describe the preparation of etoricoxib in 4 or 5 steps from 6-
methylnicotinate. The key step is the novel pyridine construction using annulation of a
ketosutfone with a vinamidinium synthon. In human whole blood, in vitro, the IC50 value
obtained for inhibition of COX-2 is 1 .I μM as compared to 116 μM obtained for inhibition of
COX-1. Thus, etoricoxib is the most selective COX-2 inhibitor to date, with a COX-IKOX-
2 ratio of IC50 values of 106 for etoricoxib as compared to 35, 30, 7.6 for rofecoxib,
valdecoxib and celecoxib, respectively. Its in vivo potency is generally comparable to that
of rofecoxib in animal models against inflammation (carrageenan-induced paw edema),
pyrexia (LPS-induced pyresis), pain (carrageenan-induced hyperalgesia) and arthritis
(adjuvant-induced arthritis). Etoricoxib is well tolerated with dose-proportional
pharmacokinetics. It has no effect on bleeding time or platelet ag regation. The
gastrointestinal tolerability of etoricoxib is excellent as demonstrated by [51Cr] models of
excretion in rats and squirrel monkeys. Moreover, etoricoxib, unlike naproxen is not
associated with significant inhibition of gastric mucosal PGE2 synthesis compared to
placebo. Etoricoxib is highly absorbed, has a tmax of 1.5 h and a half-life time of
approximately 15-22h. Five metabolites, weak inhibitors of COX-1 and COX-2 have been
identified after renal excretion. Finally, although multiple CYP enzymes are involved in the
metabolism of etoricoxib (CYP3A4 being the major contributor), etoricoxib is not a potent
CYP3A4 inhibitor or inducer. In patients undergoing molar extraction, etoricoxib showed
similar efficacy to naproxen sodium with a longer duration of analgesia than
acetaminophen/codeine (approximately ＞24 h, 22 h and 5.2 h, respectively) and a better
total pain relief score over 8 h. Similar efficacy of etoricoxib and naproxen was also seen in
patients suffering of osteoarthritis. In the treatment of rheumatoid arthritis and ankylosing
spondylitis, etoricoxib demonstrated significantly superior efficacy compared to naproxen
and placebo. Etoricoxib did not affect the pharmacokinetics of prednisolone (i.v. or p.0.)
and its co-administration with antacids showed insignificant effects on the maximal
concentration and its absorption.
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Chemical Properties
Off-White Powder
Originator
Merck & Co (USA)
Uses
A specific inhibitor of COX-2 .
Uses
anti-inflammatory, analgesic;cyclooxygenase inhibitor
Uses
Etoricoxib is a dipyridinyl compound that demonstrates high in vitro and ex vivo selectivity for COX-2 over COX-1 in several assays, e.g., in the production of PGE2 by CHO cells expressing either COX-2 (IC50 = 79 nM) or COX-1 (IC50 > 50 μM). Oral etoricoxib is well absorbed and metabolized extensively via oxidation, with metabolites excreted largely in the urine.[Cayman Chemical]
Uses
For the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout.
Uses
Labeled Etoricoxib, intended for use as an internal standard for the quantification of Etoricoxib by GC- or LC-mass spectrometry.
Definition
ChEBI: A member of the class of bipyridines that is 2,3'-bipyridine which is substituted at the 3, 5, and 6' positions by 4-(methylsulfonyl)phenyl, chlorine, and methyl groups, respectively.
Clinical Use
Etoricoxib is a selective COX-2 inhibitor being developed for postsurgical treatment of dental pain (120
mg) and osteoarthritis. It has a methylsulfonyl group common to the other coxib inhibitors.
Synthesis
The synthesis of etoricoxib (8) was explored extensively by
the Merck process research group. Key intermediate 85
was synthesized through at least three different routes. In the
Horner-Wittig approach, 6-methyl methylnicotinate (79) was
converted into Weinreb amide 80 in 95% yield. Amide 80
was then converted to aldehyde 81 via a DIBAL-H mediated
reduction. Subsequent treatment of a solution of aldehyde 81
in isopropyl acetate with aniline and diphenyl phosphite
provided N,P-acetal 82 in 87% yield. The Horner-Wittig
reaction of N,P-acetal 82 with 4-methanesulfonylbenzaldehyde
(83) furnished enamine 84, which was
hydrolyzed to ketosulfone 85. A Grignard approach was also
developed in the preparation of ketosulfone 85. Addition of
Grignard reagent 86 to Weinreb amide 80 in toluene/THF
provided ketosulfide 85 in 80% yield. Tungstate-catalyzed
oxidation of ketosulfide 87 using hydrogen peroxide
provided ketosulfone 85 in 89% yield by simple filtration.
Ketosulfone 85 was prepared through Claisen condensation
protocol as well. Thus, reaction of 4-methanesulfonyl phenyl
acetic acid (88) with methyl nicotinate 79 under Ivanoff
condition, i.e., the magnesium dianion in THF, resulted
58% yield of ketosulfone 85. Treatment of ketosulfone 85
with a three-carbon electrophile, 2-chloro-N,Ndimethylaminotrimethinium
hexafluorophos-phate (89) in
the presence of potassium t-butoxide at ambient temperature
resulted adduct 90. Inverse quench of adduct 90 into a
mixture of HOAc /TFA led to the putative intermediate 91.
Ring closure of the pyridine ring occurred upon heating at reflux in the presence of an excess of aqueous ammonium
hydroxide to give desired etoricoxib (8) in 97% yield in a
one-pot process from 85.
Metabolism
Etoricoxib is metabolized involving oxidation of its 6′-methyl group primarily by CYP3A4 but is
not an inhibitor of CYP3A4. Other metabolites include 1′-N-oxide and glucuronides. Etoricoxib is primarily excreted as
metabolites into the urine.
