8
682
S. Olgen, D. Nebiog˘lu / Il Farmaco 57 (2002) 677–683
Table 2
[2] Y. Song, D.T. Connor, A.D. Sercel, R.J. Sorenson, R. Double-
In vitro COX-2 potencies of indole esters 6–24
day, P.C. Unangst, B.D. Roth, V.G. Beylin, R.B. Gilbertsen, K.
Chan, D.J. Schrier, A. Guglietta, D.A. Bornemeier, R.D. Dyer,
Synthesis, structure activity relationships, and in vivo evalua-
tions of substituted di-tert-butylphenols as a novel class of
potent, selective, and orally active cyclooxygenase-2 inhibitors 2.
1,3,4- and 1,2,4-thiadiazole series, J. Med. Chem. 42 (1999)
1161–1169.
Comp.
IC50 (mM) a
Selectivity b
COX-2
COX-1
LM4108
Indomethacin
0.1
0.75
\66.0
0.05
\660
0.067
ND
\19.0
\11.6
[3] J.J. Talley, S.R. Bertenshaw, D.L. Brown, J.S. Carter, M.J.
Graneto, M.S. Kellogg, C.M. Koboldt, J. Yuan, Y.Y. Zhang, K.
6–19, 21, 22, 24
20
23
\50.0
2.0
ND
\38.0
\29.0
Seibert,
N-[[(5-Methyl-3-phenylisoxazol-4-yl)-pheny]sulfonyl]
2.5
propanamide, sodium salt, parecoxib sodium: a potent and
selective inhibitor of COX-2 for parenteral administration, J.
Med. Chem. 43 (2000) 1661–1663.
a IC50 values were determined by incubating concentration at 2 and
10 in mM in DMSO with human COX-2 (66 nM) or ovine COX-1 (44
nM) for 20 min at r.t. followed by initiation of the COX reaction with
the addition of 14C-AA (50 mM) at 37 °C for 30 s. Assays were run
in duplicate.
[4] T.D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W.
Collins, S. Docter, M.J. Graneto, L.F. Lee, J.W. Malecha, J.M.
Miyashiro, R.S. Rogers, D.J. Rogier, S.S. Yu, G.D. Anderson,
E.G. Burton, J.N. Cogburn, S.A. Gregory, C.M. Koboldt, W.E.
Perkins, K. Seibert, A.W. Veenhuizen, Y.Y. Zang, P.C. Isakson,
Synthesis and biological evaluation of the 1,5-diarylpyrazole
class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-
methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide (SC-58635, celecoxib), J. Med. Chem. 40 (1997) 1347–
1365.
b Ratio of IC50 (COX-1)–(COX-2).
Biological activity tests were applied by comparing
the inhibition effects of COX-2 for these compounds
with indomethacin and LM4108 that is reported by
Kalgutkar et al. [14]. Our synthesized compounds 20
and 23 were slightly active at 2 and 10 mM. The results
were summarized in Table 2. These compounds contain
cyclopropyl methyl and cyclopropyl ethyl group on the
ester side chain. However, there is no significant selec-
tivity for compounds 20 and 23, when they were com-
pared with indomethacin and LM4108. None of other
compounds were found active against COX-2 concen-
tration at 2 and 10 mM. Many ester and amide deriva-
tives were found highly active and selective to
inhibition of COX-2 enzyme in the literature [13–15].
On the contrary, it was surprising that our compounds
were not. This suggests that not all carboxylate-, ace-
tate- and propionate-containing indole derivatives can
be converted into COX-2 inhibitors by esterification.
Consequently, the results of activity tests showed that
the synthesized ester derivatives were not promising
compounds for selective COX-2 inhibition while the
amide derivatives were.
[5] D.B. Reitz, K. Seibert, Selective cyclooxygenase inhibitors,
Annu. Rep. Med. Chem. 30 (1995) 179–186.
[6] J.Y. Gauthier, Y. Lebranc, W.C. Black, C.-C. Chan, W.A.
Cromlish, R. Gordon, B.P. Kennedey, C.K. Lau, S. Leger, Z.
Wang, D. Ethier, J. Guay, J. Manchini, D. Riendeau, P. Tagari,
P. Vickers, E. Wong, L. Xu, P. Prasit, Synthesis and biological
evaluation of 2,3-diarylthiophenes as selective COX-2 inhibitors.
Part II: replacing the heterocycle, Bioorg. Med. Chem. Lett. 6
(1996) 87–92.
[7] J.J. Talley, D.L. Brown, J.S. Carter, M.J. Graneto, C.M.
Koboldt, J.L. Masferrer, W.E. Perkins, R.S. Rogers, A.F. Shaf-
fer, Y.Y. Zhang, B.S. Zweifel, K. Siebert, 4-[5-Methyl-3-pheny-
isoxazol-4-yl]-benzenesulfonamide, valdecoxib:
a potent and
selective inhibitor of COX-2, J. Med. Chem. 43 (2000) 775–777.
[8] J.S. Carter, S. Kramer, J.J. Talley, T. Penning, P. Collins, M.J.
Graneto, K. Seibert, C.M. Koboldt, J. Masferrer, B. Zweifel,
Synthesis and activity of sulfonamide substituted 4,5-diaryl thia-
zoles as selective cyclooxygenase-2 inhibitors, Bioorg. Med.
Chem. Lett. 9 (1999) 1171–1174.
[9] I.K. Khanna, R.M. Weier, Y. Yu, X.D. Xu, F.J. Koszyk, P.W.
Collins, C.M. Koboldt, A.W. Veenhuizen, W.E. Perkins, J.J.
Casler, J.L. Masferrer, Y.Y. Zhang, S.A. Gregory, K. Seibert,
P.C. Isakson, 1,2-Diarylimidazoles as potent cyclooxygenase-2.
Selective, and orally active antiinflammatory agents, J. Med.
Chem. 40 (1997) 1634–1647.
[10] D.B. Reitz, J.J. Li, M.B. Norton, E.J. Reinhard, J.T. Collins,
G.D. Anderson, S.A. Gregory, C.M. Koboldt, W.E. Perkins, K.
Seibert, P.C. Isakson, Selective cyclooxygenase inhibitors: novel
1,2-diarylcyclopentenes are potent and orally active COX-2 in-
hibitors, J. Med. Chem. 37 (1994) 3878–3881.
[11] W.C. Black, C. Bayly, M. Belley, C.-C. Chan, S. Charleson, D.
Denis, J.Y. Gauthier, R. Gordon, D. Guay, S. Kargman, C.K.
Lau, Y. Leblanc, J. Mancini, M. Ouellet, D. Percival, P. Roy, K.
Skorey, P. Tagari, P. Vickers, E. Wong, L. Xu, P. Prasit, From
indomethacin to a selective COX-2 inhibitor: development of
indolalkanoic acids as potent and selective cyclooxygenase-2
inhibitors, Bioorg. Med. Chem. Lett. 6 (1996) 725–730.
[12] B. Portevin, C. Tordjman, P. Pastoureau, J. Bonnet, G. De
Nanteuil, 1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives:
a new series of potent and selective COX-2 inhibitors in which a
sulfonyl group is not a structural requisite, J. Med. Chem. 43
(2000) 4582–4593.
Acknowledgements
This work was partially supported by a grant from
the Turkish Scientific and Technical Research Institute
(SBAG-AYD-341). The authors thank Dr Larry Mar-
nett (Vanderbilt School of Medicine, Department of
Biochemistry, Tennessee, USA) for performing some of
COX-2 enzyme inhibition tests.
References
[1] W.L. Smith, D.L. Dewitt, Prostaglandin endoperoxide H syn-
thases-1 and 2, Adv. Immunol. 62 (1996) 167–215.