Letters
The 5,7- and 4,5-dichloroindolylpiperazines (10n and
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 3959
(2) Hill, S. J .; Ganellin, C. R.; Timmerman, H.; Schwartz, J . C.;
Shankley, N. P.; Young, J . M.; Schunack, W.; Levi, R.; Haas, H.
L. International Union of Pharmacology. XIII. Classification of
histamine receptors. Pharmacol. Rev. 1997, 49, 253-278.
(3) Hough, L. B. Genomics Meets Histamine Receptors: New
Subtypes, New Receptors. Mol Pharmacol. 2001, 59, 415-419.
(4) Schneider, E.; Rolli-Derkinderen, M.; Arock, M.; Dy, M. Trends
in histamine research: new functions during immune responses
and hematopoiesis. Trends Immunol. 2002, 23, 255-263.
(5) Ash, A. S. F.; Schild, H. O. Receptors mediating some actions of
histamine. Br. J . Pharmacol. 1966, 27, 427-439.
10o, respectively) displayed high receptor affinity with
Ki’s ) 11 nM and 5 nM, respectively. The 5,7-dimethyl
compound 10p (Ki ) 31 nM) was found to be equipotent
to the 5-CH3 analogue 10g (Ki ) 46 nM) but slightly
less potent than the 7-CH3 compound 10m (Ki ) 7 nM).
A similar trend was seen for the 5,7-difluoro indolyl-
piperazine 10q when compared to its 5-fluoro analogue.
A detailed biological evaluation of 10e and 10l was
undertaken due to their high affinity for the H4 receptor.
Functional activity versus the human H4 receptor was
determined using SK-N-MC cells stably transfected with
the human H4 receptor.8 In these cells, addition of
histamine induces a decrease in the forskolin stimulated
cAMP levels. Compounds 10e and 10l produced a
rightward shift in the histamine dose response curve
yielding a pA2 ) 8.14 and 8.11, respectively, confirming
that they function as H4 receptor antagonists. These
compounds also showed high affinity for the rat hista-
mine H4 receptor24 (10e Ki ) 2.4 nM and 10l Ki ) 3.3
nM) and were found to be >1000-fold selective for the
H4 receptor over the other histamine receptors. When
tested against a panel of over 50 receptor targets
representing the major classes of biogenic amine recep-
tors, neuropeptide receptors, ion channel binding sites,
and transporters, these compounds showed minimal
biological activity.
(6) Black, J . W.; Duncan, W. A. M.; Durant, C. J .; Ganellin, C. R.;
Parsons, E. M. Definition and antagonism of histamine H2-
receptors. Nature (London) 1972, 236, 385-390.
(7) Arrang, J . M.; Garbarg, M.; Schwartz, J . C. Auto-inhibition of
brain histamine release mediated by a novel class (H3) of
histamine receptor. Nature (London) 1983, 302, 832-837.
(8) Liu, C.; Ma, X.-J .; J iang, X.; Wilson, S. J .; Hofstra, C. L.; Blevitt,
J .; Pyati, J .; Li, X.; Chai, W.; Carruthers, N.; Lovenberg, T. W.
Cloning and pharmalogical characterization of a fourth hista-
mine receptor (H4) expressed in bone marrow. Mol. Pharmacol.
2001, 59, 420-426.
(9) Morse, K. L.; Behan, J .; Laz, T. M.; West, R. E., J r.; Greenfeder,
S. A.; Anthes, J . C.; Umland, S.; Wan, Y.; Hipkin, R. W.;
Gonsiorek, W.; Shin, N.; Gustafson, E. L.; Qiao, X.; Wang, S.;
Hendrick, J . A.; Greene, J .; Bayne, M.; Monsma, F. J ., J r.
Cloning and characterization of a novel human histamine
receptor. J . Pharmacol. Exp. Ther. 2001, 296, 1058-1066.
(10) Oda, T.; Morikawa, N.; Saito, Y.; Masuho, Y.; Matsumoto, S.-i.
Molecular cloning and characterization of a novel type of
histamine receptor preferentially expressed in leukocytes. J .
Biol. Chem. 2000, 275, 36781-36786.
(11) Nguyen, T.; Shapiro, D. A.; George, S. R.; Setola, V.; Lee, D. K.;
Cheng, R.; Rauser, L.; Lee, S. P.; Lynch, K. R.; Roth, B. L.;
O′Dowd, B. F. Discovery of a novel member of the histamine
receptor family. Mol. Pharmacol. 2001, 59, 427-433
(12) Zhu, Y.; Michalovich, D.; Wu, H.-L.; Tan, K. B.; Dytko, G. M.;
Mannan, I. J .; Boyce, R.; Alston, J .; Tierney, L. A.; Li, X.; Herrity,
N. C.; Vawter, L.; Sarau, H. M.; Ames, R. S.; Davenport, C. M.;
Hieble, J . P.; Wilson, S,; Bergsma, D. J .; Fitzgerald, L. R.
Cloning, expression, and pharmacological characterization of a
novel histamine receptor. Mol. Pharmacol. 2001, 59, 434-
441.
(13) O’Reilly, M.; Alpert, R.; J enkinson, S.; Gladue, R. P.; Foo, S.;
Trim, S.; Peter, B.; Trevethick, M.; Fidock, M. Identification of
a histamine H4 receptor on human eosinophils-role in eosinophil
chemotaxis. J . Recept. Signal Tranduction Res. 2002, 22, 431-
448.
Con clu sion . After screening our corporate compound
collection against the histamine H4 receptor and iden-
tifying lead compound indolylpiperazine (6), we began
a medicinal chemistry program to improve the biological
activity of lead compound 6 and elucidate the SAR for
the series. Several general trends can be gleaned from
the results presented in Tables 1 and 2. Our SAR
investigation suggested that in order to maintain po-
tency less than 100 nM, substitution on the piperazine
nitrogen must be limited to a methyl group. In contrast,
a variety of substituents about the indole ring were well
tolerated. In general, lipophilic groups or compact polar
groups increased affinity for the H4 receptor relative to
the unsubstituted analogue. Disubstitution on the indole
ring was also tolerated, resulting in compounds with
activity comparable to the 5-substituted analogues.
Detailed biological evaluation of selected analogues,
10e and 10l, demonstrated that these ligands are
selective for the histamine H4 receptor and that they
function as receptor antagonists. Thus, we have pre-
pared the first potent and selective non-imidazole
histamine H4 antagonists. Further pharmacological
characterization of 10e, J NJ 7777120, will be reported
in due course.
(14) Hosftra, C.; Desai, P. J .; Thurmond, R. L.; Fung-Leung, W.-P.
Histamine H4 receptor mediates chemotaxis and calcium mobi-
lization of mast cells. J . Pharmacol. Exp. Ther. 2003, 305, 1212-
1221.
(15) Raible, D. G.; Lenahan, T.; Fayvilevich, Y.; Kosinski, R.; Schul-
man, E. S. Pharmacologic characterization of a novel histamine
receptor on human eosinophils. Am. J . Respir. Crit. Care Med.
1994, 149, 1506-1511.
(16) Ganter, F.; Sakai, K.; Tusche, M. W.; Cruikshank, W. W.; Center,
D. M.; Bacon, K. B. Histamine H4 and H2 receptors control
histamine-induced interleukin-16 release from human CD8+
T
cells. J . Pharmacol. Exp. Ther. 2002, 303, 300-307.
(17) Raible, D. G.; Schulman, E. S.; DiMuzio, J .; Cardillo, R.; Post,
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3542.
(18) (a) Schwartz, J . C.; Arrang, J .-M.; Garbarg, M.; Lecomte, J .-M.;
Ligneau, X.; Schunack, W. G.; Stark, H.; Ganellin, C. R.;
Leurquin, F.; Sigurd, E. Nonimidazole alkylamines as histamine
H3-receptor ligands and their therapeutic applications. 1998,
European patent #0982300A2. (b) Ganellin, C. R.; Leurquin, F.;
Piripitsi, A.; Arrang, J .-M.; Garbarg, M.; Ligneau, X.; Stark, H.;
Schunack, W.; Schwartz, J . C. The discovery of potent non-
imidazole H3-receptor histamine antagonists. In Histamine
Research in the New Millenium; Watanabe, T., Timmerman, H.,
Yanai, K., Eds.; Elsevier: New York, 2001; pp 25-31.
(19) Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May,
P. D.; Palmer, J . R.; J ohnson, P. D.; Smith, H. W.; Busso, M.;
Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey,
K. M.; So, A. G.; Resnick, L.; Tarpley, W. G.; Aristoff, P. A. Dis-
covery, synthesis, and bioactivity of bis(heteroaryl)piperazines.
1. A novel class of nonnucleoside HIV-1 reverse transcriptase
inhibitors. J . Med. Chem. 1994, 37, 999-1014.
Ack n ow led gm en t. The authors thank Drs. Richard
Apodaca and Emily Stocking for careful reading of this
manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical data for target compounds are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Bhandari, K.; Murti, V. A.; J ain, P. C.; Anand, D. Agents acting
on the CNS: Part XXXIII. Synthesis of 1,2,3,4,6,7,8,12c-octa-
hydropyrazino[2′,1′:2,1]pyrido[4,3-b]indole and some 2-substi-
tuted aminoalkylindoles. Ind. J . Chem., Sec. B. 1979, 17B, 246-
249.
Refer en ces
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