Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4713
(15) Erlanson, D. A. Fragment-based lead discovery: a chemical up-
date. Curr. Opin. Biotechnol. 2006, 17, 643–652.
(16) Abad-Zapatero, C.; Metz, J. T. Ligand efficiency indices as guide-
posts for drug discovery. Drug Discovery Today 2005, 10, 464–469.
(17) Makara, G. M. On sampling of fragment space. J. Med. Chem.
2007, 50, 3214–3221.
(18) Bemis, G. W.; Murcko, M. A. The properties of known drugs. 1.
Molecular frameworks. J. Med. Chem. 1996, 39, 2887–2893.
(19) Duarte, C. D.; Barreiro, E. J.; Fraga, C. A. Privileged structures: a
useful concept for the rational design of new lead drug candidates.
Mini-Rev. Med. Chem. 2007, 7, 1108–1119.
(35) Djuric, S. W.; Huff, R. M.; Penning, T. D.; Clare, M.; Swenton, L.;
Kachur, J. F.; Villani-Price, D.; Krivi, G. G.; Pyla, E. Y.; Warren,
T. G. Synthesis and pharmacological activity of rationally designed
inhibitors of the leukotriene A4 hydrolase enzyme. Bioorg. Med.
Chem. 1992, 2, 1367–1370.
(36) Fretland, D. J.; Anglin, C. P.; Bremer, M.; Isakson, P.; Widomski,
D. L.; Paulson, S. K.; Docter, S. H.; Djuric, S. W.; Penning, T. D.;
Yu, S. Antiinflammatory effects of second-generation leukotriene
B4 receptor antagonist, SC-53228: impact upon leukotriene B4-
and 12(R)-HETE-mediated events. Inflammation 1995, 19, 193–
205.
(20) Muller, G. Medicinal chemistry of target family-directed master-
(37) Penning, T. D.; Djuric, S. W.; Miyashiro, J. M.; Yu, S.; Snyder, J.
P.; Spangler, D.; Anglin, C. P.; Fretland, D. J.; Kachur, J. F.;
Keith, R. H.; et al. Second-generation leukotriene B4 receptor
antagonists related to SC-41930: heterocyclic replacement of the
methyl ketone pharmacophore. J. Med. Chem. 1995, 38, 858–868.
(38) Penning, T. D.; Djuric, S. W.; Docter, S. H.; Yu, S. S.; Spangler, D.;
Anglin, C. P.; Fretland, D. J.; Kachur, J. F.; Keith, R. H.; Tsai, B.
S. The design and synthesis of second generation leukotriene B4
(LTB4) receptor antagonists related to SC-41930. Agents Actions
1993, 39 Spec. No., C11–C13.
(39) Grice, C. A.; Tays, K. L.; Savall, B. M.; Wei, J.; Butler, C. R.; Axe,
F. U.; Bembenek, S. D.; Fourie, A. M.; Dunford, P. J.; Lundeen,
K.; Coles, F.; Xue, X.; Riley, J. P.; Williams, K. N.; Karlsson, L.;
Edwards, J. P. Identification of a potent, selective, and orally active
leukotriene A4 hydrolase inhibitor with anti-inflammatory activ-
ity. J. Med. Chem. 2008, 51, 4150–4169.
keys. Drug Discovery Today 2003, 8, 681–691.
(21) Siegel, M. G.; Vieth, M. Drugs in other drugs: a new look at drugs
as fragments. Drug Discovery Today 2007, 12, 71–79.
(22) Smith, E.; Morowitz, H. J. Universality in intermediary metabo-
lism. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 13168–13173.
(23) Binkowski, T. A.; Joachimiak, A. Protein functional surfaces:
global shape matching and local spatial alignments of ligand
binding sites. BMC Struct. Biol. 2008, 8, 45.
(24) Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F.
3rd; Schenck, R. J.; Trippe, A. J. Structural diversity of organic
chemistry. A scaffold analysis of the CAS Registry. J. Org. Chem.
2008, 73, 4443–4451.
(25) Kull, F.; Ohlson, E.; Haeggstrom, J. Z. Cloning and characteriza-
tion of a bifunctional leukotriene A(4) hydrolase from Sacchar-
omyces cerevisiae. J. Biol. Chem. 1999, 274, 34683–34690.
(26) Thunnissen, M. M.; Nordlund, P.; Haeggstrom, J. Z. Crystal
structure of human leukotriene A(4) hydrolase, a bifunctional
enzyme in inflammation. Nat. Struct. Biol. 2001, 8, 131–135.
(27) Tholander, F.; Muroya, A.; Roques, B. P.; Fournie-Zaluski, M. C.;
Thunnissen, M. M.; Haeggstrom, J. Z. Structure-based dissection
of the active site chemistry of leukotriene A4 hydrolase: implica-
tions for M1 aminopeptidases and inhibitor design. Chem. Biol.
2008, 15, 920–929.
(28) Qiu, H.; Gabrielsen, A.; Agardh, H. E.; Wan, M.; Wetterholm, A.;
Wong, C. H.; Hedin, U.; Swedenborg, J.; Hansson, G. K.;
Samuelsson, B.; Paulsson-Berne, G.; Haeggstrom, J. Z. Expression
of 5-lipoxygenase and leukotriene A4 hydrolase in human athero-
sclerotic lesions correlates wtih symptoms of plaque instability.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8161–8166.
(40) Kirkland, T. A.; Adler, M.; Bauman, J. G.; Chen, M.; Haeggstrom,
J. Z.; King, B.; Kochanny, M. J.; Liang, A. M.; Mendoza, L.;
Phillips, G. B.; Thunnissen, M.; Trinh, L.; Whitlow, M.; Ye, B.; Ye,
H.; Parkinson, J.; Guilford, W. J. Synthesis of glutamic acid
analogs as potent inhibitors of leukotriene A4 hydrolase. Bioorg.
Med. Chem. 2008, 16, 4963–4983.
(41) Ye, B.; Bauman, J.; Chen, M.; Davey, D.; Khim, S. K.; King, B.;
Kirkland, T.; Kochanny, M.; Liang, A.; Lentz, D.; May, K.;
Mendoza, L.; Phillips, G.; Selchau, V.; Schlyer, S.; Tseng, J. L.;
Wei, R. G.; Ye, H.; Parkinson, J.; Guilford, W. J. Synthesis of N-
alkyl glycine amides as potent inhibitors of leukotriene A4 hydro-
lase. Bioorg. Med. Chem. Lett. 2008, 18, 3891–3894.
(42) Khim, S. K.; Bauman, J.; Evans, J.; Freeman, B.; King, B.;
Kirkland, T.; Kochanny, M.; Lentz, D.; Liang, A.; Mendoza, L.;
Phillips, G.; Tseng, J. L.; Wei, R. G.; Ye, H.; Yu, L.; Parkinson, J.;
Guilford, W. J. Discovery of novel and potent aryl diamines as
leukotriene A4 hydrolase inhibitors. Bioorg. Med. Chem. Lett.
2008, 18, 3895–3898.
(43) Sandanayaka, V.; Mamat, B.; Mishra, R. K.; Winger, J.; Krohn,
M.; Zhao, L.-M.; Kevan, M.; Enache, L.; D., S.; Onua, E.; Zhang,
J.; Halldorsdottir, G.; Sigthorsdottir, H.; Thorlaksdottir, A.;
Sigthorsson, G.; Thorsteinnsdottir, M.; Davies, D. R.; Stewart,
L. J.; Zembower, D. E.; Andresson, T.; Kiselyov, A. S.; Singh, J.;
Gurney, M. E. Discovery of DG-051 as a novel leukotriene A4
hydrolase inhibitor of leukotriene B4 biosynthesis. Unpublished
results, 2009.
(44) Schorlemmer, H. U.; Bosslet, K.; Dickneite, G.; Luben, G.;
Sedlacek, H. H. Studies on the mechanisms of action of the
immunomodulator bestatin in various screening test systems.
Behring Inst. Mitt. 1984, 157–173.
(45) Tholander, F.; Kull, F.; Ohlson, E.; Shafqat, J.; Thunnissen, M.
M.; Haeggstrom, J. Z. Leukotriene A4 hydrolase, insights into the
molecular evolution by homology modeling and mutational ana-
lysis of enzyme from Saccharomyces cerevisiae. J. Biol. Chem. 2005,
280, 33477–33486.
(46) Haeggstrom, J. Z. Leukotriene A4 hydrolase/aminopeptidase, the
gatekeeper of chemotactic leukotriene B4 biosynthesis. J. Biol.
Chem. 2004, 279, 50639–50642.
(47) Yokomizo, T.; Kato, K.; Terawaki, K.; Izumi, T.; Shimizu, T. A
second leukotriene B(4) receptor, BLT2. A new therapeutic target
in inflammation and immunological disorders. J. Exp. Med. 2000,
192, 421–432.
(29) Helgadottir, A.; Manolescu, A.; Helgason, A.; Thorleifsson, G.;
Thorsteinsdottir, U.; Gudbjartsson, D. F.; Gretarsdottir, S.;
Magnusson, K. P.; Gudmundsson, G.; Hicks, A.; Jonsson, T.;
Grant, S. F.; Sainz, J.; O’Brien, S. J.; Sveinbjornsdottir, S.;
Valdimarsson, E. M.; Matthiasson, S. E.; Levey, A. I.; Abramson,
J. L.; Reilly, M. P.; Vaccarino, V.; Wolfe, M. L.; Gudnason, V.;
Quyyumi, A. A.; Topol, E. J.; Rader, D. J.; Thorgeirsson, G.;
Gulcher, J. R.; Hakonarson, H.; Kong, A.; Stefansson, K. A variant
of the gene encoding leukotriene A4 hydrolase confers ethnicity-
specific risk of myocardial infarction. Nat. Genet. 2006, 38, 68–74.
(30) Sanchez-Galan, E.; Gomez-Hernandez, A.; Vidal, C.; Martin-
Ventura, J. L.; Blanco-Colio, L. M.; Munoz-Garcia, B.; Ortega,
L.; Egido, J.; Tunon, J. Leukotriene B4 enhances the activity of
nuclear factor-kappaB pathway through BLT1 and BLT2 recep-
tors in atherosclerosis. Cardiovasc. Res. 2009, 81, 216–225.
(31) Holloway, J. W.; Barton, S. J.; Holgate, S. T.; Rose-Zerilli, M. J.;
Sayers, I. The role of LTA4H and ALOX5AP polymorphism in
asthma and allergy susceptibility. Allergy 2008, 63, 1036–1053.
(32) Penning, T. D.; Chandrakumar, N. S.; Desai, B. N.; Djuric, S. W.;
Gasiecki, A. F.; Malecha, J. W.; Miyashiro, J. M.; Russell, M. A.;
Askonas, L. J.; Gierse, J. K.; Harding, E. I.; Highkin, M. K.;
Kachur, J. F.; Kim, S. H.; Villani-Price, D.; Pyla, E. Y.;
Ghoreishi-Haack, N. S.; Smith, W. G. Synthesis of imidazopyr-
idines and purines as potent inhibitors of leukotriene A4 hydrolase.
Bioorg. Med. Chem. Lett. 2003, 13, 1137–1139.
(33) Penning, T. D.; Chandrakumar, N. S.; Desai, B. N.; Djuric, S. W.;
Gasiecki, A. F.; Liang, C. D.; Miyashiro, J. M.; Russell, M. A.;
Askonas, L. J.; Gierse, J. K.; Harding, E. I.; Highkin, M. K.;
Kachur, J. F.; Kim, S. H.; Villani-Price, D.; Pyla, E. Y.; Ghoreishi-
Haack, N. S.; Smith, W. G. Pyrrolidine and piperidine analogues of
SC-57461A as potent, orally active inhibitors of leukotriene A(4)
hydrolase. Bioorg. Med. Chem. Lett. 2002, 12, 3383–3386.
(34) Penning, T. D.; Chandrakumar, N. S.; Chen, B. B.; Chen, H. Y.;
Desai, B. N.; Djuric, S. W.; Docter, S. H.; Gasiecki, A. F.; Haack,
R. A.; Miyashiro, J. M.; Russell, M. A.; Yu, S. S.; Corley, D. G.;
Durley, R. C.; Kilpatrick, B. F.; Parnas, B. L.; Askonas, L. J.;
Gierse, J. K.; Harding, E. I.; Highkin, M. K.; Kachur, J. F.; Kim, S.
H.; Krivi, G. G.; Villani-Price, D.; Pyla, E. Y.; Smith, W. G.
Structure-activity relationship studies on 1-[2-(4-phenylphen-
oxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene
A(4) (LTA(4)) hydrolase. J. Med. Chem. 2000, 43, 721–735.
(48) Yokomizo, T.; Izumi, T.; Chang, K.; Takuwa, Y.; Shimizu, T. A
G-Protein-coupled receptor for leukotriene B4 that mediates che-
motaxis. Nature 1997, 387, 620–624.
(49) Tryselius, Y.; Nilsson, N. E.; Kotarsky, K.; Olde, B.; Owman, C.
Cloning and characterization of cDNA encoding a novel human
leukotriene B(4) receptor. Biochem. Biophys. Res. Commun. 2000,
274, 377–382.
(50) Kamohara, M.; Takasaki, J.; Matsumoto, M.; Saito, T.; Ohishi, T.;
Ishii, H.; Furuichi, K. Molecular cloning and characterization of
another leukotriene B4 receptor. J. Biol. Chem. 2000,275, 27000–27004.
(51) Lundeen, K. A.; Sun, B.; Karlsson, L.; Fourie, A. M. Leukotriene
B4 receptors BLT1 and BLT2: expression and function in human
and murine mast cells. J. Immunol. 2006, 177, 3439–3447.