N-[[(5-methyl-3-phenylisoxazol-4-yl)phenyl] sulfonyl]propanamide, sodium salt, parecoxib sodium: A potent and selective inhibitor of COX-2 for parenteral administration

Full text of DOI:10.1021/jm000069h

J . Med. Chem. 2000, 43, 1661-1663
1661
Communications to the Editor
N-[[(5-Meth yl-3-p h en ylisoxa zol-4-yl)-
p h en yl]su lfon yl]p r op a n a m id e, Sod iu m
Sa lt, P a r ecoxib Sod iu m : A P oten t a n d
Selective In h ibitor of COX-2 for
P a r en ter a l Ad m in istr a tion
the elderly; reduction of renal function, potentially
leading to fluid retention and exacerbation of hyper-
tension; and inhibition of platelet function, potentially
predisposing to increased operative bleeding.9
-11
Ketorolac is a potent inhibitor of both COX-1 and COX-
12
2
.
In general, COX-2 inhibitors of the diarylheterocycle
J ohn J . Talley,* Stephen R. Bertenshaw,
David L. Brown, J effery S. Carter,
class such as 1 and 2 possess modest aqueous solubility.
This physicochemical characteristic restricts the dosing
options available for this class of drug. In considering
the development of a COX-2 inhibitor for parenteral
administration, we wondered if a prodrug of a sulfon-
amide-based inhibitor could be designed which would
possess the appropriate combination of aqueous solubil-
ity and in vivo antiinflammatory activity. Herein we
describe our efforts that culminated in the identification
of the injectable COX-2 inhibitor parecoxib sodium (5b).
Matthew J . Graneto, Michael S. Kellogg,
†
Carol M. Koboldt, J inhua Yuan, Yan Y. Zhang, and
Karen Seibert
Searle Research and Development, 700 Chesterfield
Parkway, St. Louis, Missouri 63198, and 4901 Searle
Parkway, Skokie, Illinois 60077
Received February 18, 2000
In tr od u ction . Increased risk for gastrointestinal
ulceration is associated with blockade of cyclooxyge-
nase-1 (COX-1) derived prostaglandins.1 Until very
recently, all commercially available nonsteroidal anti-
inflammatory drugs (NSAIDs) were inhibitors of both
COX-1 and COX-2. Selective inhibitors of COX-2 are
now widely recognized as offering the promise of treat-
ment of inflammatory conditions without the side effects
associated with consumption of nonselective inhibi-
tors. Celecoxib (1) and rofecoxib (2) recently were
the first two highly selective COX-2 inhibitors to be
approved in selected markets for the treatment of
certain inflammatory conditions.
Ch em istr y. Acylation of isoxazole sulfonamide 4 with
an anhydride in the presence of triethylamine afforded
the corresponding acylated sulfonamide. The sodium
salt was then prepared by titration of the acylated
sulfonamide with aqueous sodium hydroxide to afford
the requisite sodium salts 5, Scheme 1.
Resu lts a n d Discu ssion . An important criterion
that we established for a parenteral COX-2 inhibitor
was for it to possess sufficient analgesic potency such
that patients could be dosed with a minimal injection
volume. Large injection volumes can be time consuming
and may contribute to discomfort for patients. Meeting
the criterion of a small injection volume dictated that
only very potent compounds would be ideal for this
application. Among the most potent and selective COX-2
inhibitors that have been identified is the isoxazole
sulfonamide valdecoxib (4). Against recombinant human
cyclooxygenase isoforms, 4 showed the following activ-
ity: hCOX-1 IC50 ) 140 µM and hCOX-2 IC50 ) 0.005
µM. In addition, 4 possesses exceptional antiinflamma-
2
,3
4
5
1
3
tory activity in vivo. Our strategy to develop an
injectable COX-2 inhibitor commenced with the idea of
identifying a water-soluble prodrug of 4 that would
undergo biotransformation in vivo. To test whether an
1
4,15
acylated sulfonamide
would serve as a prodrug for
4
, 5a was prepared as described above and evaluated
in vitro and in vivo. To our considerable satisfaction,
the solubility of 5a in phosphate-buffered saline at 25
To date, relatively few NSAIDs may be administered
parenterally for the treatment of pain and inflamma-
tion. One of the most effective nonnarcotic analgesics
for the treatment of moderate to severe acute pain,
°C was found to be quite substantial, 44 mg/mL. Against
the recombinant isoforms of human cyclooxygenases, 5a
was found to show very weak inhibitory activity, hCOX-1
IC50 f 100 µM and hCOX-2 IC50 f 20 µM. However, in
6
-8
particularly postsurgical pain, is ketorolac (3).
Al-
though very effective as an analgesic, ketorolac use is
associated with a significant incidence of untoward side
effects. The most common side effects associated with
ketorolac consumption are increased risk for upper
gastrointestinal ulceration and bleeding, particularly in
16
the carrageenan air pouch model of inflammation, 5a
showed potent antiinflammatory activity after intra-
venous, intramuscular, or oral administration, ED50 )
0
.5 mg/kg.
The ample antiinflammatory activity of 5a suggested
that the acyl moiety was cleaved in vivo. To confirm this
hypothesis, the pharmacokinetics and metabolic profile
of 5a were examined. It was found that the half-life for
*
To whom correspondence should be addressed. Tel: 636-737-7373.
Fax: 636-737-7425. E-mail: john.j.talley@monsanto.com.
†
Searle Research and Development, Illinois.
1
0.1021/jm000069h CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/05/2000

1
662 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 9
Communications to the Editor
Sch em e 1
F igu r e 1. Pharmacokinetic profile of the conversion of pare-
coxib sodium (5b) (9) to valdecoxib (4) (O) in male rats.
the conversion of 5a to 4 was about 15 min in rats.
However, when 5a was administered either intrave-
nously or orally to canines or cynomolgus monkeys, it
was found that 5a was not completely converted to 4
and a significant amount of compound was eliminated
in the urine unchanged. The attractive antiinflamma-
tory activity of 5a in rodents warranted evaluation of
the congeners 5b and 5c in the rodent, dog, and monkey.
Fortunately, in these three species both 5b and 5c were
rapidly and completely converted to 4. In addition, in
vitro metabolic studies with human liver microsomes
showed that both 5b and 5c were completely converted
to 4. Owing to the more favorable solubility of 5b (22
mg/mL at 25 °C) versus 5c (10 mg/mL at 25 °C) in
phosphate-buffered saline, a more through assessment
of the biological activity 5b was conducted.
F igu r e 2. Time course for the reversal of hyperalgesia and
prostaglandin production after intravenous administration of
ketorolac (3).
Pharmacokinetic studies of 5b were conducted in vivo
in the rat, dog, and cynomolgus monkey to determine
the rate and extent of its conversion to 4. The in vivo
conversion of 5b was complete and rapid after intra-
venous administration to male rats (mean elimination
half-life ) 0.135 ( 0.003 h), female dogs (0.553 ( 0.009
h), and female cynomolgus monkeys (1.21 ( 0.004 h).
Shown in Figure 1 is the pharmacokinetic profile of 5b
in rodents. In vivo administration of 5b demonstrated
its bioequivalence to orally administered 4. Chronic
antiinflammatory activity was achieved in the rat
F igu r e 3. Time course for the reversal of hyperalgesia and
prostaglandin production after intravenous administration of
parecoxib sodium (5b).
reached a maximal response, 5b was administered
intravenously and the reversal of hyperalgesia mea-
sured. Shown in Figures 2 and 3 are the results of
administration of 30 mg/kg ketorolac compared with the
same dose of 5b. When dosed therapeutically, ketorolac
(30 mg/kg) rapidly and completely inhibited the pain
response. The activity of 5b at 30 mg/kg in this model
compared favorably with the activity of ketorolac,
producing a complete blockade of the carrageenan-
induced hyperalgesia within 1 h after intravenous
administration (Figure 3). The ED50 for 5b in this model
was 5 mg/kg, with a maximal analgesic response
1
7
adjuvant arthritis model, ED50 ) 0.08 mg/kg. Acute
antiinflammatory activity of 5b was demonstrated in
the carrageenan air pouch assay, 98% inhibition at 0.3
mg/kg.
Intravenous administration of 5b showed consider-
able activity in an acute analgesic assay (carrageenan
foot pad edema).1
8,19
The analgesic efficacy as well as
the onset of action of 5b was assessed in a therapeutic
8
paradigm. Three hours after administration of carra-
geenan to the hind foot pad of rats results in maximal
edema and pain response. When edema and pain

Communications to the Editor
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 9 1663
achieved within 1 h of administration, indicating that
it possesses a potent and fast-acting analgesic pharma-
cological profile.
Pena, A.; Perez, V.; Valdez, D.; Ackerman, N.; Ballaron, S. A.;
Krishna Murthy, D. V.; Rovito, J . R.; Tomolonis, A. J .; Young,
J . M.; Rooks, W. H. Synthesis and Antiinflammatory and
Analgesic Activity of 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyr-
role-1-carboxylic Acids and Related Compounds. J . Med. Chem.
Con clu sion s. The availability of a safe and effica-
cious injectable COX-2 inhibitor for acute pain manage-
ment, particularly postsurgical pain, constitutes an
important unmet medical need. Parecoxib sodium, 5b,
a water-soluble prodrug of valdecoxib, 4, was identified
as a highly potent and selective inhibitor of PGs from
COX-2. In a therapeutic model of acute pain, parecoxib
sodium showed excellent efficacy and a rapid onset of
action comparable with the most potent analgesic
NSAID ketorolac. Parecoxib sodium is currently in
clinical evaluation for the management of acute pain.
1
985, 28, 1037-1049.
(
7) Guzman, A.; Yuste, F.; Toscano, R. A.; Young, J . M.; Van Horn,
A. R.; Muchowski, J . M. Absolute Configuration of (-)-5-Benzoyl-
1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic Acid, the Ac-
tive Enantiomer of Ketorolac. J . Med. Chem. 1986, 29, 589-
5
91.
(
8) Zhang, Y.; Shaffer, A.; Portanova, J .; Seibert, K.; Isakson, P.
Inhibition of Cyclooxygenase-2 Rapidly Reverses Inflammatory
2
Hyperalgesia and Prostaglandin E Production. J . Pharmacol.
Exp. Ther. 1997, 283, 1069-1075.
(
9) Strom, B. L.; Berlin, J . A.; Kinman, J . L.; Spitz, P. W.; Hennessy,
S.; Feldman, H.; Kimmel, S.; Carson, J . L. Parenteral ketorolac
and risk of gastro-intestinal and oprative side bleeding:
postmarketing survey. J . Am. Med. Assoc. 1996, 275, 376-382.
10) Choo, V.; Lewis, S. Ketorolac doses reduced. Lancet 1993, 342,
09.
11) Lewis, S. Ketorolac in Europe. Lancet 1994, 343, 784.
A
(
(
Su p p or tin g In for m a tion Ava ila ble: Biological proce-
dures, synthetic procedures, and spectral data for compounds
1
5
a -5c are available free of charge via the Internet at http://
(12) J ett, M. F.; Ramesha, C. S.; Brown, C. D.; Chiu, S.; Emmett, C.;
Voronin, T.; Sun, T.; O’Yang, C.; Hunter, J . C.; Eglen, R. M.;
J ohnson, R. M. Characterization of the Analgesic and Antiin-
flammatory Activities of Ketorolac and Its Enantiomers in the
Rat. J . Pharmacol. Exp. Ther. 1999, 288, 1288-1297.
pubs.acs.org.
Refer en ces
(
1) DeWitt, D. L. Cox-2 Selective Inhibitors: The New Super
Aspirins. Mol. Pharmacol. 1999, 55, 625-631.
(13) Talley, J . J .; Brown, D. L.; Carter, J . S.; Graneto, M. J .; Koboldt,
C. M.; Masferrer, J . L.; Perkins, W. E.; Rogers, R. S.; Shaffer,
A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. 4-[5-Methyl-3-
phenylisoxazol-4-yl]benzenesulfonamide, Valdecoxib: A Potent
and Selective Inhibitor of COX-2. J . Med. Chem. 2000, 43, 775-
(
2) Talley, J . J . Selective Inhibitors of COX-2. In Progress in
Medicinal Chemistry 36; King, F. D., Oxford, A., Eds.; Elsevier:
Amsterdam, 1999; pp 201-234.
(
3) Kalgutkar, A. S. Selective cyclooxygenase-2 inhibitors as non-
ulcerogenic antiinflammatory agents. Exp. Opin. Ther. Patents
7
77.
(
(
(
14) Larsen, J . D.; Bundgaard, H. Prodrug forms of the sulfonamide
group. I. Evaluation of N-acyl derivatives, N-sulfonamidines,
N-sulfonylsulfilimines and sulfonylureas as possible prodrug
derivatives. Int. J . Pharm. 1987, 37, 87-95.
15) Larsen, J . D.; Bundgaard, H.; Lee, V. H. L. Prodrug forms for
the sulfonamide group. II. Water soluble amino acid derivatives
of N-methylsulfonamides as possible prodrugs. Int. J . Pharm.
1
999, 8, 831-849.
(
4) Penning, T. D.; Talley, J . J .; Bertenshaw, S. R.; Carter, J . S.;
Collins, P. W.; Docter, S.; Graneto, M. J .; Lee, L. F.; Malecha, J .
W.; Miyahiro, J . M.; Rogers, R. S.; Rogier, D. J .; Yu, S. S.;
Anderson, G. D.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. Synthesis and
Biological Evaluation of the 1,5-Diarylpyrazole Class of Cy-
clooxygenase-2 Inhibitors: Identification of 4-[5-(4-Methylphe-
nyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-
1
988, 47, 103-110.
16) Masferrer, J . L.; Zweifel, B. S.; Manning, P. T.; Hauser, S. D.;
Leahey, K. M.; Smith, W. G.; Isakson, P. C.; Seibert, K. Selective
Inhibition of Inducible Cyclooxygenase-2 In Vivo is Antiinflam-
matory and Nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A. 1994,
5
8635, Celecoxib). J . Med. Chem. 1997, 40, 1347-1365.
(
5) Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson, S.;
Cromlish, W.; Ethier, D.; Evans, J . F.; Ford-Hutchinson, A. W.;
Gauthier, J . Y.; Gordon, R.; Guay, J .; Gresser, M.; Kargman, S.;
Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J .; O’Neil, G. P.;
Ouellet, M.; Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger,
I.; Tagari, P.; Therien, M.; Vickers, P.; Wong, E.; Xu, L.-J .;
Young, R. N.; Zamboni, R.; Boyce, S.; Rupniak, N.; Forrest, M.;
Visco, D.; Patrick, D. The discovery of rofecoxib, [MK 966, Vioxx,
9
1, 3228-3232.
(17) J affee, B. D.; Kerr, J . S.; J ones, E. A.; Giannaras, J . V.;
McGowan, M.; Ackerman, N. R. The Effect of Immunomodulat-
ing Drugs on Adjuvant-induced Arthritis in Lewis Rats. Agents
Actions 1989, 27, 344-346.
(18) Winter, C. A.; Risley, E. A.; Nuss, G. W. Carrageenan-Induced
Edema in Hind Paw of the Rat as an Assay for Antiinflammatory
Drugs. Proc. Soc. Exp. Biol. Med. 1962, 305, 479-484.
(19) Hargreaves, K.; Dubner, R.; Brown, F.; Flores, C.; J oris, J . A.
New and Sensitive Method for Measuring Thermal Nociception
in Cutaneous Hyperalgesia. Pain 1988, 32, 77-88.
4
-(4′-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally
active cyclooxygenase-2 inhibitor. Bioorg. Med. Chem. Lett. 1999,
, 1773-1778.
9
(
6) Muchowski, J . M.; Unger, S. H.; Ackrell, J .; Cheung, P.; Cooper,
G. F.; Cook, J .; Gallegra, P.; Halpern, O.; Koehler, R.; Kluge, A.
F.; Van Horn, A. R.; Antonio, Y.; Carpio, H.; Franco, F.; Galeazzi,
E.; Garcia, I.; Greenhouse, R.; Guzman, A.; Iriarte, J .; Leon, A.;
J M000069H