SAR Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 735
(9) (a) Haeggstro¨m, J . Z.; Wetterholm, A.; Vallee, B. L.; Samuelsson,
B. Leukotriene A4 Hydrolase: An Epoxide Hydrolase with
Peptidase Activity. Biochem. Biophys. Res. Commun. 1990, 173,
431-437. (b) Minami, M.; Bito, H.; Ohishi, N.; Tsuge, H.;
Miyano, M.; Mori, M.; Wada, H.; Mutoh, H.; Shimada, S.; Izumi,
T.; Abe, K.; Shimizu, T. Leukotriene A4 Hydrolase, a Bifunctional
Enzyme. FEBS 1992, 309, 353-357. (c) Haeggstro¨m, J . Z.;
Wetterholm, A.; Medina, J . F.; Samuelsson, B. Leukotriene A4
Hydrolase: Structural and Functional Properties of the Active
Center. J . Lipid Mediators 1993, 6, 1-13.
(10) (a) Izumi, T.; Shimizu, T.; Seyama, Y.; Ohishi, N.; Takaku, F.
Tissue Distribution of Leukotriene A4 Hydrolase Activity in
Guinea Pig. Biochem. Biophys. Res. Commun. 1986, 135, 139-
145. (b) Fu, J . Y.; Haeggstro¨m, J .; Collins, P.; Meijer, J .;
Rådmark, O. Leukotriene A4 Hydrolase: Analysis of Some
Human Tissues by Radioimmunoassay. Biochim. Biophys. Acta
1989, 1006, 121-126.
P h en ylcycloh exa n ol. To a solution of 4-phenylcyclohexanone
(1.7 g, 10 mmol) in EtOH (30 mL) was added a solution of
NaBH4 (0.3 g, 7.9 mmol) in water (3 mL), and the mixture
was stirred at 25 °C for 1 h. The mixture was poured into 1 N
HCl and EtOAc, and the organic layer was washed with brine,
dried over Na2SO4, and concentrated. Flash chromatography
on silica gel using a gradient of 5:1 to 3:1 hexane/EtOAc gave
the cis-product (0.184 g, 10.4%) as a white solid [1H NMR
(CDCl3) δ 1.45 (s, 1H), 1.69 (m, 4H), 1.90 (m, 4H), 2.53 (tt, J
) 11.7, 2.9 Hz, 1H), 4.14 (br, 1H), 7.26 (m, 5H)] and the trans-
product (0.50 g, 28.4%) as a white solid [1H NMR (CDCl3) δ
1.49 (m, 4H), 1.86 (s, 1H), 1.96 (m, 2H), 2.12 (m, 2H), 2.51 (tt,
J ) 11.7, 3.3 Hz, 1H), 3.69 (tt, J ) 10.4, 4.3 Hz, 1H), 7.26 (m,
5H)].
Step 2: P r ep a r a tion of 1-[2-[(tr a n s-4-P h en yl)cyclo-
h exyloxy]eth yl]p yr r olid in e. To a solution of the trans-
product from step 1 (0.48 g, 2.7 mmol) in DMF (25 mL) was
added 0.22 g of NaH (60% dispersion in oil, 5.5 mmol), and
the mixture stirred at 25 °C for 45 min. 1-(2-Chloroethyl)-
pyrrolidine‚HCl (0.48 g, 2.8 mmol) and n-Bu4NI (1.04 g, 2.8
mmol) were added, and the mixture was stirred at 25 °C for
24 h and at 80 °C for 15 h. The mixture was poured into Et2O
and water, and the ether layer was washed with brine, dried
over Na2SO4, and concentrated. Flash chromatography on
silica gel using a gradient of 2:1 hexane/EtOAc to 100% EtOAc
gave 30 (0.283 g, 38%) as a yellow oil: 1H NMR (CDCl3) δ 1.42
(m, 4H), 1.77 (m, 4H), 1.91 (m, 2H), 2.16 (m, 2H), 2.48 (m,
1H), 2.55 (m, 4H), 2.69 (t, J ) 6 Hz, 2H), 3.29 (m, 1H), 3.64 (t,
J ) 6 Hz, 2H), 7.22 (m, 5H). Anal. (C18H27NO‚0.2H2O) C, H,
N.
(11) (a) Fu, J . Y.; Medina, J . F.; Funk, C. D.; Wetterholm, A.;
Rådmark, O. Leukotriene A4, Conversion to Leukotriene B4 in
Human T-cell Lines. Prostaglandins 1988, 36, 241-248. (b)
Lindgren, J . A.; Edenius, C. Transcellular Biosynthesis of
Leukotrienes and Lipoxins Via Leukotriene A4 Transfer. Trends
Pharmacol. Sci. 1993, 14, 351-354.
(12) 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.; and
Warren, T. G. Synthesis and Pharmacological Activity of Ratio-
nally Designed Inhibitors of the Leukotriene A4 Hydrolase
Enzyme. Bioorg. Med. Chem. Lett. 1992, 2, 1367-1370.
(13) Labaudinie`re, R.; Hilboll, G.; Leon-Lomeli, A.; Lautenschla¨ger,
H.-H.; Parnham, M.; Kuhl, P.; Dereu, N. ω-[(ω-Arylalkyl)aryl]-
alkanoic Acids:
A New Class of Specific LTA4 Hydrolase
Inhibitors. J . Med. Chem. 1992, 35, 3156-3169.
(14) (a) Orning, L.; Krivi, G.; Fitzpatrick, F. A. Leukotriene A4
Hydrolase: Inhibition by Bestatin and Intrinsic Aminopeptidase
Activity Establish its Functional Resemblance to Metallohydro-
lase Enzymes. J . Biol. Chem. 1991, 266, 1375-1378. (b) Evans,
J . F.; Kargman, S. Bestatin Inhibits Covalent Coupling of [3H]-
LTA4 to Human Leukocyte LTA4 Hydrolase. FEBS 1992, 297,
139.
Ack n ow led gm en t. We thank Kathryn A. House-
man for providing the ACE and NEP data on selected
compounds.
(15) (a) Orning, L.; Krivi, G.; Bild, G.; Gierse, J .; Aykent, S.;
Fitzpatrick, F. A. Inhibition of Leukotriene A4 Hydrolase/
Aminopeptidase by Captopril. J . Biol. Chem. 1991, 266, 16507-
16511. (b) Shindo, K.; Baker, J . R.; Munafo, D. A.; Bigby, T. D.
Captopril Inhibits Neutrophil Synthesis of Leukotriene B4 In
Vitro and In Vivo. J . Immunol. 1994, 5750-5759.
(16) Yuan, W.; Munoz, B.; Wong, C. H.; Haeggstro¨m, J . Z.; Wetter-
holm, A.; Samuelsson, B. Development of Selective Tight-Binding
Inhibitors of Leukotriene A4 Hydrolase. J . Med. Chem. 1993,
36, 211-220.
(17) (a) Ollmann, I. R.; Hogg, J . H.; Bunoz, B.; Haeggstro¨m, J . Z.;
Sameulsson, B.; Wong, C.-H. Investigation of the Inhibition of
Leukotriene A4 Hydrolase. Bioorg. Med. Chem. 1995, 3, 969-
995. (b) Hogg, J . H.; Ollmann, I. R.; Haeggstro¨m, J . Z.; Wetter-
holm, A.; Samuelsson, B.; Wong, C.-H. Amino Hydroxamic Acids
as Potent Inhibitors of Leukotriene A4 Hydrolase. Bioorg. Med.
Chem. 1995, 3, 1405-1415. (c) Wetterholm, A.; Haeggstro¨m, J .
Z.; Samuelsson, B.; Yuan, W.; Munoz, B.; Wong, C.-H. Potent
and Selective Inhibitors of Leukotriene A4 Hydrolase: Effects
on Purified Enzyme and Human Polymorphonuclear Leukocytes.
J . Pharmacol. Exp. Ther. 1995, 275, 31-37. (d) Hogg, J . H.;
Ollmann, O. R.; Wetterholm, A.; Andberg, M. B.; Haeggstro¨m,
J .; Sameulsson, B.; Wong, C.-H. Probing the Activities and
Mechanisms of Leukotriene A4 Hydrolase with Synthetic Inhibi-
tors. Chem. Eur. J . 1998, 4, 1698-1713.
(18) Penning, T. D.; Askonas, L. J .; Djuric, S. W.; Haack, R. A.; Yu,
S. S.; Michener, M. L.; Krivi, G. G.; Pyla, E. Y. Kelatorphan and
Related Analogues: Potent and Selective Inhibitors of Leuko-
triene A4 Hydrolase. Bioorg. Med. Chem. Lett. 1995, 5, 2517-
2522.
(19) Tsuji, F.; Miyake, Y.; Horiuchi, M.; Mita, S. Involvement of
Leukotriene B4 in Murine Dermatitis Models. Biochem. Phar-
macol. 1998, 55, 297-304.
(20) Parnas, B. L.; Durley, R. C.; Rhoden, E. E.; Kilpatrick, B. F.;
Makkar, N.; Thomas, K. E.; Smith, W. G.; Corley, D. G. Isolation
and Structure of Leukotriene-A4 Hydrolase Inhibitor: 8(S)-
Amino-2(R)-methyl-7-oxononanoic Acid Produced by Streptomy-
ces diastaticus. J . Nat. Prod. 1996, 59, 962-964.
Refer en ces
(1) Bray, M. A. Leukotrienes in Inflammation. Agents Actions 1986,
19, 87-99.
(2) (a) Lewis, R. A.; Austin, K. F.; Soberman, R. J . Leukotrienes
and Other Products of the 5-Lipoxygenase Pathway. N. Engl.
J . Med. 1990, 323, 645-655. (b) Henderson, W. R. The Role of
Leukotrienes in Inflammation. Ann. Intern. Med. 1994, 121,
684-697.
(3) Sharon, P.; Stenson, W. F. Enhanced Synthesis of Leukotriene
B4 by Colonic Mucosa in Inflammatory Bowel Disease. Gastro-
enterology 1984, 86, 453-460.
(4) (a) Barr, R. M.; Wong E, Mallet, A. I.; Olins, L. A.; Greaves, M.
W. The Analysis of Arachidonic Acid Metabolites in Normal,
Uninvolved and Lesional Psoriatic Skin. Prostaglandins 1984,
28, 57-65. (b) Grimminger, F.; Mayser, P. Lipid Mediators, Free
Fatty Acids and Psoriasis. Prost. Leuk. Essen. Fatty Acids 1995,
52, 1-15. (c) Iversen, L.; Kragballe, K.; Ziboh, V. A. Significance
of Leukotriene A4 Hydrolase in the Pathogenesis of Psoriasis.
Skin Pharmacol. 1997, 10, 169-177.
(5) Klickstein, L. B.; Shapleigh, C.; Goetzl, E. J . Lipoxygenation of
Arachidonic Acid as a Source of Polymorphonuclear Leukocyte
Chemotactic Factors in Synovial Fluid and Tissue in Rheumatoid
Arthritis and Spondyloarthritis. J . Clin. Invest. 1980, 66, 1166-
1170.
(6) Rae, S. A.; Davidson, E. M.; Smith, M. J . H. Leukotriene B4, an
Inflammatory Mediator in Gout. Lancet 1982, 11, 1122-1123.
(7) (a) Drazen, J . M.; Dahlen, S.-E.; Lee, T. H., Eds. Five-Lipoxy-
genase Products in Asthma; Marcell Dekker: New York, 1998.
(b) O’Driscoll, B. R. C.; Cromwell, O.; Kay, A. B. Sputum
Leukotrienes in Obstructive Airways Diseases. Clin. Exp. Im-
munol. 1984, 55, 397-404. (c) Bigby, T. D.; Lee, D. M.; Meslier,
N.; Gruenert, D. C. Leukotriene A4 Hydrolase Activity of Human
Airway Epithelial Cells. Biochem. Biophys. Res. Commun. 1989,
164, 1-7.
(8) (a) Funk, C. D.; Rådmark, O.; Fu, J . Y.; Matsumoto, T.; J o¨rnvall,
H.; Shimizu, T.; Samuelsson, B. Molecular Cloning and Amino
Acid Sequence of Leukotriene A4 Hydrolase. Proc. Natl. Acad.
Sci. U.S.A. 1987, 84, 6677-6681. (b) Toh, H.; Minami, M.;
Shimizu, T. Molecular Evolution and Zinc Ion Binding Motif of
Leukotriene A4 Hydrolase. Biochem. Biophys. Res. Commun.
1990, 171, 216-221. (c) Haeggstro¨m, J . Z.; Wetterholm, A.;
Shapiro, R.; Vallee, B. L.; Samuelsson, B. Leukotriene A4
Hydrolase: A Zinc Metalloenzyme. Biochem. Biophys. Res.
Commun. 1990, 172, 965-970. (d) Minami, M.; Ohishi, N.;
Mutoh, H.; Izumi, T.; Bito, H.; Wada, H.; Seyama, Y.; Toh, H.;
Shimizu, T. Leukotriene A4 Hydrolase is a Zinc-containing
Aminopeptidase. Biochem. Biophys. Res. Commun. 1990, 173,
620-626.
(21) Gierse, J . K.; Luckow, V. A.; Askonas, L. J .; Duffin, K. L.; Aykent,
S.; Bild, G. S.; Rodi, C. P.; Sullivan, P. M.; Bourner, M. J .;
Kimack, N. M.; Krivi, G. G. High Level Expression and Purifica-
tion of Human Leukotriene A4 Hydrolase From Insect Cells
Infected With a Baculovirus Vector. Protein Expression Purif.
1993, 4, 358-366.
(22) Portoghese, P. S.; Mikhail, A. A. Bicyclic Bases. Synthesis of 2,5-
Diazabicyclo[2.2.1] heptanes. J . Org. Chem. 1966, 31, 1059-1061.
J M990496Z