Meta-Substituted Aryl(thio) Ethers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3273
piperidine. J . Med. Chem. 1994, 37, 332-333. (b) Shih, N. Y.;
Lupo, A. T.; Aslanian, R.; Orlando, S.; Piwinski, J . J .; Green,
M. J .; Ganguly, A. K.; Clark, M. A.; Tozzi, S.; Kreutner, W.; Hey,
J . A. A Novel Pyrrolidine Analog of Histamine as a Potent,
Highly Selective Histamine H3 Receptor Agonist. J . Med Chem.
1995, 38, 1593-1599.
Schlicker, E.; Kathmann, M.; Bitschnau, H.; Marr, I.; Reide-
meister, S.; Stark, H.; Schunack, W. Potencies of Antagonists
Chemically Related to Iodoproxyfan at Histamine H3 Receptors
in Mouse Brain Cortex and Guinea-Pig Ileum: Evidence for H3
Receptor Heterogeneity? Naunyn-Schmiedeberg’s Arch. Phar-
macol. 1996 353, 482-488. (c) Wulff, B. S.; Hastrup, S.; Rimvall,
K. Characteristics of recombinantly expressed rat and human
histamine H3 receptors. Eur. J . Pharmacol. 2002, 453, 33-41.
(d) Low, C. M. R.; Vinter, J . G.; Kalindjian, S. B.; Pether, M. J .
The Molecular Origins of Agonism at Histamine H3-Receptors:
An Investigation of Agonist Behaviour in Halogenated Deriva-
tives of Proxyfan, 3-(1H-Imidazol-4-yl)propylphenylmethyl ether.
Presented at the British Pharmacological Society Autumn
Meeting, Edinburgh, September 1-4, 1997; Poster P151; Br. J .
Pharmacol. 1997, 122 (Suppl.), 433P. (e) Watt, G. F.; Sykes, D.
A.; Roberts, S. P.; Shankley, N. P.; Black, J . W. Estimation of
Agonist Affinity and Efficacy Parameters of Histamine H3-
Receptor Ligands in Guinea-Pig Ileum. Br. J . Pharmacol. 1997,
122 (Suppl.), 435. (f) Lovenberg, T. W.; Pyati, J .; Chang, H.;
Wilson, S. J .; Erlander, M. G. Cloning of Rat Histamine H3
Receptor Reveals Distinct Species Pharmacological Profiles. J .
Pharmacol. Exp. Ther. 2000, 293, 771-778. (g) Chen, J .; Liu,
C.; Lovenberg, T. W. Molecular and Pharmacological Charac-
terization of the Mouse Histamine H3 Receptor. Eur. J . Phar-
macol. 2003, 467, 57-65.
(10) (a) Harusawa, S.; Imazu, T.; Takashima, S.; Araki, L.; Ohishi,
H.; Kurihara, T.; Yamamoto, Y.; Yamatodani, A. Synthesis of
Imifuramine and Its Stereoisomers Exhibiting Histamine H3-
Agonist Activity. Tetrahedron Lett. 1999, 40, 2561-2564. (b)
Kazuta, Y.; Hirano, K.; Natsume, K.; Yamada, S.; Kimura, R.;
Matsumoto, S.; Furuichi, K.; Matsuda, A.; Shuto, S. Cyclopro-
pane-Based Conformational Restriction of Histamine. (1S,2S)-
2-(2-Aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a Highly Se-
lective Agonist for the Histamine H3 Receptor, Having a cis-
Cyclopropane Structure. J . Med. Chem. 2003, 46, 1980-
1988.
(11) (a) Vollinga, R. C.; Menge, W. M. P. B.; Leurs, R.; Timmerman,
H. Homologs of Histamine H3 Receptor Antagonists. A New
Potent and Selective H3 Antagonist, 4(5)-(5-Aminopentyl)-1H-
imidazole J . Med. Chem. 1995, 38, 266-271. (b) Leurs, R.;
Kathmann, M.; Vollinga, R. C.; Menge, W. M. P. B.; Schlicker,
E.; Timmerman, H. Histamine Homologues Discriminating
between Two Functional H3 Receptor Assays. Evidence for H3
Receptor Heterogeneity? J . Pharmacol. Exp. Ther 1996, 276,
1009-1015.
(18) Vollinga, R. C.; Zuiderveld, O. P.; Scheerens, H.; Bast, A.;
Timmerman, H. A Simple and Rapid in Vitro Test System for
the Screening of Histamine H3 Ligands. Methods Find. Exp.
Clin. Pharmacol. 1992, 14, 747-751.
(19) (a) Ligneau, X.; Garbarg, M.; Vizuete, M. L.; Diaz, J .; Purand,
K.; Stark, H.; Schunack, W.; Schwartz, J .-C. [125I]Iodoproxyfan,
a New Antagonist To Label and Visualize Cerebral Histamine
(12) (a) Gros, J .; Manning, B. S.; Pietri-Rouxel, F.; Guillaume, J .-L.;
Drumare, M.-F.; Strosberg, A. D. Site-Directed Mutagenesis of
the Human â3-Adrenoceptor. Transmembrane Residues Involved
in Ligand Binding and Signal Transduction. Eur. J . Biochem.
1988, 251, 590-596. (b) Fraser, C. M.; Wang, C.-D.; Robinson,
D. A.; Gocayne, J . D.; Venter, J . C. Site-Directed Mutagenesis
of the m1 Muscarinic Receptor; Conserved Aspartic Acids Play
Important Roles in Receptor Function. Mol. Pharmacol. 1989,
36, 840-847. (c) J ackson, T. Structure and Function of G Protein
Coupled Receptors. Pharmacol. Ther. 1991, 50, 425-442. (d)
Beck-Sickinger, A. G. Structural Characterization and Binding
Sites of G-Protein Coupled Receptors. Drug Discovery Today
1996, 1, 502-513.
H
3 Receptors. J . Pharmacol. Exp. Ther. 1994, 271, 452-459. (b)
Stark, H.; Purand, K.; Hu¨ls, A.; Ligneau, X.; Garbarg, M.;
Schwartz, J .-C.; Schunack, W. [125I] Iodoproxyfan and Related
Compounds: A Reversible Radioligand and Novel Classes of
Antagonists with High Affinity and Selectivity for the Histamine
H3 Receptor. J . Med. Chem. 1996, 39, 1220-1226.
(20) (a) Ganellin, C. R.; Fkyerat, A.; Bang-Andersen, B.; Athmani,
S.; Tertiuk, W.; Garbarg, M.; Ligneau, X.; Schwartz, J .-C. A
Novel Series of (Phenoxyalkyl)imidazoles as Potent H3-Receptor
Histamine Antagonists. J . Med. Chem. 1996, 39, 3806-3813.
(b) Ligneau, X.; Lin, J .-S.; Vanni-Mercier, G.; J ouvet, M.; Muir,
J . L.; Ganellin, C. R.; Stark, H.; Elz, S.; Schunack, W.; Schwartz,
J .-C. Neurochemical and Behavioral Effects of Ciproxifan, a
Potent Histamine H3 Receptor Antagonist. J . Pharmacol. Exp.
Ther. 1998, 287, 658-666. (c) Stark, H.; Sadek, B.; Krause, M.;
Hu¨ls, A.; Ligneau, X.; Ganellin, C. R.; Arrang, J .-M.; Schwartz,
J .-C.; Schunack, W. Novel Histamine H3-Receptor Antagonists
with Carbonyl-Substituted 4-(3-(Phenoxypropyl)-IH-imidazole
Structures Like Ciproxifan and Related Compounds. J . Med.
Chem. 2000, 43, 3987-3994. (d) Sasse, A.; Sadek, B.; Ligneau,
X.; Elz, S.; Pertz, H. H.; Luger, P.; Ganellin, C. R.; Arrang, J .-
M.; Schwartz, J .-C.; Schunack, W. New Histamine H3-Receptor
Ligands of the Proxifan Series: Imoproxifan and Other Selective
Antagonists with High Oral in Vivo Potency. J . Med. Chem.
2000, 43, 3335-3343.
(13) (a) Ohta, K.; Hayashi, H.; Mizuguchi, H.; Kagamiyama, H.;
Fujimoto, K.; Fukui, H. Site-Directed Mutagenesis of the His-
tamine H1 Receptor: Roles of Aspartic Acid107, Asparagine198 and
Threonine194
. Biochem. Biophys. Res. Commun. 1994, 203,
1096-1101. (b) Wieland, K.; Laak, A. M. T.; Smit, M. J .; Kuhne,
R.; Timmerman, H.; Leurs, R. Mutational Analysis of the
Antagonist-Binding of the Histamine H1 Receptor. J . Biol. Chem.
1999, 274, 29994-30000. (c) Gantz, I.; DelValle, J .; Wang, L.-
D.; Tashiro, T.; Munzert, G.; Guo, Y.-J .; Konda, Y.; Yamada, T.
Molecular Basis for the Interaction of Histamine with the
Histamine H2 Receptor. J . Biol. Chem. 1992, 267, 20840-20843.
(d) Shin, N.; Coates, E.; Murgolo, N. J .; Morse, K. L.; Bayne,
M.; Strader, C. D.; Monsma, F. J . Molecular Modeling and Site-
Specific Mutagenesis of the Histamine-Binding Site of the
Histamine H4 Receptor. Mol. Pharmacol. 2002, 62, 38-47. (e)
Lovenberg, T. W.; Roland, B. L.; Wilson, S. J .; J iang, X.; Pyati,
J .; Huvar, A.; J ackson, M. R.; Erlander, M. G. Cloning and
Functional Expression of the Human Histamine H3 Receptor.
Mol. Pharmacol. 1999, 55, 1101-1107.
(14) (a) Sasse, A.; Stark, H.; Reidemeister, S.; Hu¨ls, A.; Elz, S.;
Ganellin, C. R.; Ligneau, X.; Schwartz, J .-C.; Schunack, W. Novel
Partial Agonists for the Histamine H3 Receptor with High in
Vitro and in Vivo Activity. J . Med. Chem. 1999, 42, 4269-4274.
(b) Sasse, A.; Stark, H; Ligneau, X.; Elz, S.; Reidemeister, S.;
Ganellin, C. R.; Schwartz, J .-C.; Schunack, W. (Partial) Agonist/
Antagonist Properties of Novel Diarylalkyl Carbamates on
Histamine H3 Receptors. Bioorg. Med. Chem. 2000, 8, 1139-
1149. (c) Sasse, A.; Ligneau, X.; Rouleau, A.; Elz, S.; Ganellin,
C. R.; Arrang, J .-M.; Schwartz, J .-C.; Schunack, W.; Stark, H.
Influence of Bulky Substituents on Histamine H3 Receptor
Agonist/Antagonist Properties. J . Med. Chem. 2002, 45, 4000-
4010.
(15) Schunack, W.; Sasse, A.; Stark, H.; Elz, S.; Ligneau, X.; Ganellin,
C. R.; Schwartz, J .-C. Partial Agonists for the Histamine H3
Receptor with High in Vivo Activity. In Histamine Reasearch
in the New Millenium; Watanabe, T., Timmerman, H., Yanai,
K., Eds.; Elsevier Science B.V.: Amsterdam, 2001; pp 77-82.
(16) (a) Van der Vliet, A.; Van der Werf, J . F.; Bast, A.; Timmerman,
H. Frequency-Dependent Autoinhibition of Histamine Release
from Rat Cortical Slices: A Possible Role for H3 Receptor
Reserve. J . Pharm. Pharmacol. 1988, 40, 577-579. (b) Leurs,
R.; Smit, M. J .; Timmerman, H. Molecular Pharmacological
Aspects of Histamine Receptors. Pharmacol. Ther. 1995, 66,
413-463.
(21) (a) Mitsunobu, O. The Use of Diethyl Azodicarboxylate and
Triphenylphosphine in Synthesis and Transformation of Natural
Products. Synthesis 1981, 1-28. (b) Hughes, D. L. The Mit-
sunobu Reaction. Org. React. 1992, 42, 335-656.
(22) Williamson, A. About the Theory of the Formation of Ethers.
Ann. Chem. 1851, 77, 37-49.
(23) Vollinga, R. C.; Menge, W. M. P. B.; Timmerman, H. A New
Convenient Route for the Synthesis of 4(5)-(ω-Aminoalkyl)-1-
H-imidazoles. Recl. Trav. Chim. Pays-Bas. 1993, 112, 123-
125.
(24) Griffith, R. K.; DiPietro, R. A. Improved Synthesis of Vinylimi-
dazoles. Synth. Commun. 1986, 16, 1761-1770.
(25) Pauling, L. The Nature of the Chemical Bond; Cornell Univer-
sity: Ithaca, NY, 1960; pp 224-229.
(26) Schwartz, J .-C.; Pollard, H.; Bischoff, S.; Rehault, M. C.; Ver-
diere, M. Catabolism of 3H-Histamine in the Rat Brain after
Intracisternal Administration. Eur. J . Pharmacol. 1971, 16,
326-335.
(27) J ensen, T. S. Synthesis of Imidazole Derivatives Acting at
Histamine H3 Receptors. M.Sc. Thesis, University College,
London, 1995; pp 73-75.
(28) (a) Watt, G. F.; Hamilton, L. C.; Shankley, N. P.; Black, J . W.
Analysis of H1-, H2- and H3-Receptor-Mediated Components of
the Response to Histamine in Guinea-Pig Isolated Ileum. Br. J .
Pharmacol. 1997, 122 (Suppl.), 435. (b) Result provided by Dr.
Gillian F. Watt, J ames Black Foundation, London, U.K.
(29) (a) Ligneau, X.; Morisset, S.; Tardivel-Lacombe, J .; Gbahou, F.;
Ganellin, C. R.; Stark, H.; Schunack, W.; Schwartz, J .-C.; Arrang,
J .-M. Distinct Pharmacology of Rat and Human Histamine H3
(17) (a) Gbahou, F.; Rouleau, A.; Morisset, S.; Parmentier, R.;
Crochet, S.; Lin, J .-S.; Ligneau, X.; Tardivel-Lacombe, J .; Stark,
H.; Schunack, W.; Ganellin, C. R.; Schwartz, J .-C.; Arrang, J .-
M. Protean Agonism at Histamine H3 Receptors in Vitro and in
Vivo. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 11086-11091. (b)