Journal of Medicinal Chemistry
ARTICLE
PRIN-06, and Aureliasan GmbH (Tuebingen, Germany) is
gratefully acknowledged.
(13) Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. Recent
developments in fragment-based drug discovery. J. Med. Chem. 2008, 51,
3661–3680.
(14) Shelke, S. V.; Cutting, B.; Jiang, X.; Koliwer-Brandl, H.;
Strasser, D. S.; Schwardt, O.; Kelm, S.; Ernst, B. A fragment-based in
situ combinatorial approach to identify high-affinity ligands for un-
known binding sites. Angew. Chem., Int. Ed. Engl. 2010, 49, 5721–5725.
(15) Nestler, H. P. Combinatorial chemistry and fragment screen-
ing—Two unlike siblings? Curr. Drug Discovery Technol. 2005, 2, 1–12.
(16) Mamidyala, S. K.; Finn, M. G. In situ click chemistry: Probing
the binding landscapes of biological molecules. Chem. Soc. Rev. 2010, 39,
1252–1261.
’ ABBREVIATIONS USED
GSH, tripeptide glutathione; MAPEG, membrane-associated
proteins in eicosanoid and glutathione metabolism; MGST-1,
microsomal glutathione transferase 1; mPGES-1, microsomal
prostaglandin E2 synthase; 5-LO, 5-lipoxygenase; FLAP, 5-lipoxy-
genase-activating protein; COX, cyclooxygenase; PG, prosta-
glandin; LT, leukotriene; LTCS, leukotrien C synthase; IL-1β,
interleukin 1β; PDB, protein data bank; NSAID, nonsteroi-
dal anti-inflammatory drug; QM, quantum mechanic; SAR,
structure-activity relationship; QSAR, quantitative structure-
activity relationship; HTS, high-throughput screening; DMF,
dimethylformamide; THF, tetrahydrofuran; DIPEA, N,N-diiso-
propylethylamine; DMSO, dimethylsulfoxide; NBS, N-bromo-
succinimide
(17) Moses, J. E.; Moorhouse, A. D. The growing applications of
click chemistry. Chem. Soc. Rev. 2007, 36, 1249–1262.
(18) Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R. Fragment-
based lead discovery. Nat. Rev. Drug Discovery 2004, 3, 660–672.
(19) Kolb, H. C.; Sharpless, K. B. The growing impact of click
chemistry on drug discovery. Drug Discovery Today 2003, 8, 1128–1137.
(20) Pasha, F. A.; Muddassan, M.; Jung, H.; Yang, B. S.; Lee, C.; Soo
Oh, J.; Joo Cho, S.; Cho, H. QM and pharmacophore based 3D-QSAR of
MK886 analogues against mPGES-1. Bull. Korean Chem. 2008, 29, 647–
655.
(21) Giroux, A.; Boulet, L.; Brideau, C.; Chau, A.; Claveau, D.; Cote,
B.; Ethier, D.; Frenette, R.; Gagnon, M.; Guay, J.; Guiral, S.; Mancini, J.;
Martins, E.; Masse, F.; Methot, N.; Riendeau, D.; Rubin, J.; Xu, D.; Yu,
H.; Ducharme, Y.; Friesen, R. W. Discovery of disubstituted phenan-
threne imidazoles as potent, selective and orally active mPGES-1
inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 5837–5841.
(22) Wang, J.; Limburg, D.; Carter, J.; Mbalaviele, G.; Gierse, J.;
Vazquez, M. Selective inducible microsomal prostaglandin E(2)
synthase-1 (mPGES-1) inhibitors derived from an oxicam template.
Bioorg. Med. Chem. Lett. 2010, 20, 1604–1609.
(23) San Juan, A. A.; Cho, S. J. 3D-QSAR study of microsomal
prostaglandin E2 synthase (mPGES-1) inhibitors. J. Mol. Model. 2007,
13, 601–610.
(24) AbdulHameed, M. D.; Hamza, A.; Liu, J.; Huang, X.; Zhan,
C. G. Human microsomal prostaglandin E synthase-1 (mPGES-1)
binding with inhibitors and the quantitative structure-activity correla-
tion. J. Chem. Inf. Model. 2008, 48, 179–185.
(25) San Juan, A. A.; Cho, S. J.; Cho, H. HQSAR study of micro-
somal prostaglandin E2 synthase (mPGES-1) inhibitors. Bull. Korean
Chem. Soc. 2006, 27, 1531–1536.
(26) Calvin, Y. A. A. Pharmacoinformatics approach for mPGES-1 in
anti-inflammation by 3D-QSAR pharmacophore mapping. J. Taiwan
Inst. Chem. 2009, 40, 155–161.
(27) Rorsch, F.; Wobst, I.; Zettl, H.; Schubert-Zsilavecz, M.; Grosch,
S.; Geisslinger, G.; Schneider, G.; Proschak, E. Nonacidic inhibitors
of human microsomal prostaglandin synthase 1 (mPGES 1) identified
by a multistep virtual screening protocol. J. Med. Chem. 2010, 53, 911–
915.
(28) Cote, B.; Boulet, L.; Brideau, C.; Claveau, D.; Ethier, D.;
Frenette, R.; Gagnon, M.; Giroux, A.; Guay, J.; Guiral, S.; Mancini, J.;
Martins, E.; Masse, F.; Methot, N.; Riendeau, D.; Rubin, J.; Xu, D.; Yu,
H.; Ducharme, Y.; Friesen, R. W. Substituted phenanthrene imidazoles
as potent, selective, and orally active mPGES-1 inhibitors. Bioorg. Med.
Chem. Lett. 2007, 17, 6816–6820.
(29) Hamza, A.; AbdulHameed, M. D.; Zhan, C. G. Understanding
microscopic binding of human microsomal prostaglandin E synthase-1
with substrates and inhibitors by molecular modeling and dynamics
simulation. J. Phys. Chem. B 2008, 112, 7320–7329.
(30) Hamza, A.; Tong, M.; AbdulHameed, M. D. M.; Liu, J.; Goren,
A. C.; Tai, H. H.; Zhan, C. G. Understanding microscopic binding of
human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with
substrate PGH2 and cofactor GSH: insights from computational alanine
scanning and site-directed mutagenesis. J. Phys. Chem. 2010, 114, 5605–
5616.
’ REFERENCES
(1) Funk, C. D. Prostaglandins and leukotrienes: Advances in
eicosanoid biology. Science 2001, 294, 1871–1875.
(2) Wang, D.; Dubois, R. N. Prostaglandins and cancer. Gut 2006,
55, 115–122.
(3) Buttgereit, F.; Burmester, G. R.; Simon, L. S. Gastrointestinal toxic
side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-
2-specific inhibitors. Am. J. Med. 2001, 110 (Suppl. 3A), 13S–19S.
(4) McGettigan, P.; Henry, D. Cardiovascular risk and inhibition of
cyclooxygenase: a systematic review of the observational studies of
selective and nonselective inhibitors of cyclooxygenase 2. J. Am. Med.
Assoc. 2006, 296, 1633–1644.
(5) Claveau, D.; Sirinyan, M.; Guay, J.; Gordon, R.; Chan, C. C.;
Bureau, Y.; Riendeau, D.; Mancini, J. A. Microsomal prostaglandin E
synthase-1 is a major terminal synthase that is selectively up-regulated
during cyclooxygenase-2-dependent prostaglandin E2 production in
the rat adjuvant-induced arthritis model. J. Immunol. 2003, 170, 4738–
4744.
(6) Yoshimatsu, K.; Golijanin, D.; Paty, P. B.; Soslow, R. A.;
Jakobsson, P. J.; DeLellis, R. A.; Subbaramaiah, K.; Dannenberg, A. J.
Inducible microsomal prostaglandin E synthase is overexpressed in
colorectal adenomas and cancer. Clin. Cancer Res. 2001, 7, 3971–3976.
(7) Yoshimatsu, K.; Altorki, N. K.; Golijanin, D.; Zhang, F.; Jakobs-
son, P. J.; Dannenberg, A. J.; Subbaramaiah, K. Inducible prostaglandin E
synthase is overexpressed in non-small cell lung cancer. Clin. Cancer Res.
2001, 7, 2669–2674.
(8) Mehrotra, S.; Morimiya, A.; Agarwal, B.; Konger, R.; Badve, S.
Microsomal prostaglandin E2 synthase-1 in breast cancer: A potential
target for therapy. J. Pathol. 2006, 208, 356–363.
(9) Jakobsson, P. J.; Thoren, S.; Morgenstern, R.; Samuelsson, B.
Identification of human prostaglandin E synthase: A microsomal,
glutathione-dependent, inducible enzyme, constituting a potential novel
drug target. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 7220–7225.
(10) Friesen, R. W.; Mancini, J. A. Microsomal prostaglandin E2
synthase-1 (mPGES-1): A novel anti-inflammatory therapeutic target.
J. Med. Chem. 2008, 51, 4059–4067.
(11) Murakami, M.; Naraba, H.; Tanioka, T.; Semmyo, N.; Nakata-
ni, Y.; Kojima, F.; Ikeda, T.; Fueki, M.; Ueno, A.; Oh, S.; Kudo, I.
Regulation of prostaglandin E2 biosynthesis by inducible membrane-
associated prostaglandin E2 synthase that acts in concert with cycloox-
ygenase-2. J. Biol. Chem. 2000, 275, 32783–32792.
(12) Jegerschold, C.; Pawelzik, S. C.; Purhonen, P.; Bhakat, P.;
Gheorghe, K. R.; Gyobu, N.; Mitsuoka, K.; Morgenstern, R.; Jakobsson,
P. J.; Hebert, H. Structural basis for induced formation of the inflam-
matory mediator prostaglandin E2. Proc. Natl. Acad. Sci. U.S.A. 2008,
105, 11110–11115.
(31) Quraishi, O.; Mancini, J. A.; Riendeau, D. Inhibition of inducible
prostaglandin E(2) synthase by 15-deoxy-Delta(12,14)-prostaglandin
1574
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