Histamine H3 and H4 receptor affinity of branched 3-(1H-imidazol-4-yl)propyl N-alkylcarbamates

Article abstract of DOI:10.1016/j.bmcl.2009.10.005

A series of imidazole-containing (non-)chiral carbamates were tested at human histamine H₃ receptor (H₃R). All compounds displayed K_i values below 100 nM. A trend for a stereoselectivity at human H₃R was observed for the chiral α-branched ligands. Selected compounds were also tested at human histamine H₄ receptor and showed moderate to weak affinities (118-1460 nM).

Full text of DOI:10.1016/j.bmcl.2009.10.005

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6682–6685
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
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Histamine H3 and H4 receptor affinity of branched 3-(1H-imidazol-4-yl)propyl
N-alkylcarbamates
a
a
b
c
c
d
_
Dorota Łazewska , Małgorzata Wie˛cek , Xavier Ligneau , Tim Kottke , Lilia Weizel , Roland Seifert ,
e
c
a,
*
´
Walter Schunack , Holger Stark , Katarzyna Kiec-Kononowicz
a Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, ul. Medyczna 9, 30-688 Kraków, Poland
b Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint-Grégoire, France
c Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 9, 60438 Frankfurt/Main, Germany
d Institute of Pharmacology, Medical School of Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
e Institute of Pharmacy, Free University of Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of imidazole-containing (non-)chiral carbamates were tested at human histamine H3 receptor
Received 23 June 2009
Revised 30 September 2009
Accepted 1 October 2009
Available online 6 October 2009
(H3R). All compounds displayed Ki values below 100 nM. A trend for a stereoselectivity at human H3R
was observed for the chiral
a-branched ligands. Selected compounds were also tested at human hista-
mine H4 receptor and showed moderate to weak affinities (118–1460 nM).
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Histamine H3 receptor
Histamine H4 receptor
Imidazole derivatives
Imidazole moiety is present in many biologically active com-
pounds (for review see1). One of the most important of them is his-
tamine. Histamine exerts tremendous influence over a variety of
physiological processes by the four known receptors subtypes:
H1, H2, H3 and H4.
scribed a series of N-methylimidazole-containing compounds—po-
tent H3R ligands with improved metabolic stability. (e.g., 1, Fig. 2)13
Histamine H4 receptors (H4Rs) are preferentially expressed on
hematopoietic and immune cells (e.g., eosinophils, mast cells, mac-
rophages) and play a role in immunological and inflammatory
processes.14
The human H4R is closely related to the human H3R. These two
proteins have a sequence identity of 31% and their homology in the
transmembrane region is 54%.15
Therefore, it is not surprising, that numerous imidazole-con-
taining H3R ligands have also significant affinity for the human
H4R (e.g., Table 1)16 and some of them (e.g., thioperamide, cloben-
propit) have been used to characterize the H4R. While the current
medicinal chemistry efforts are concerned at finding more selec-
tive compounds, AstraZeneca continues to develop imidazole
derivatives acting as dual H3R and H4R ligands (e.g., Fig. 3).17 These
compounds are considered as potential drugs for the treatment of
histamine H4 mediated diseases especially asthma. Also, very
recently, Igel et al. described NG-alkanoyl-imidazolylpropylguani-
dines as high-affinity human H3R antagonists/partial agonists and
full H4R agonists.18 For example, UR-PI294 with NG-propionyl
group, was tritiated, resulting the radioligand [3H]UR-PI294.19 This
radioligand is considered a valuable pharmacological tool for the
determination of human H3R and human H4R affinities.
Histamine H3 receptors (H3Rs) are widely expressed in CNS and
play the main role in many important processes. Nowadays, the cur-
rentinterestintheareaofH3Rligands(inverseagonists, antagonists)
is focused on non-imidazole compounds (for review see2–7),
whereas the first generation H3R active structures contained the
imidazole moiety (for review see8). These compounds were ana-
logues of histamine with the 4-substituted imidazole ring. However,
despite their high potency and clinical studies none of them have en-
tered the market as a drug. The main drawback of these compounds
was inhibition of numerous CYP450 enzymes9,10 (although recently
some studies suggested the possibilities to minimize these activi-
ties11), reduced oral bioavailability and poor brain penetration
(e.g., thioperamide12). Actually, imidazole-based ligands like thio-
peramide, clobenpropit, and ciproxifan (Fig. 1) are mainly used as
reference structures in a variety of preclinical animal models.
Despite that imidazole-containing ligands are further the
subject of investigations and quite recently, Jablonowski et al. de-
In this Letter, we describe human H3R affinity of branched
3-(1H-imidazol-4-yl)-propyl N-alkylcarbamates (Scheme 1). Most
* Corresponding author. Tel.: +48 12 620 55 81; fax: +48 12 620 55 96.
E-mail address: mfkonono@cyf-kr.edu.pl (K. Kiec´-Kononowicz).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.005

_
D. Łazewska et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6682–6685
6683
Figure 1. Some reference imidazole-containing histamine H3 receptor ligands.
O
N
O
N
N
Cl
H 3R:
human K i = 3 nM
rat pA2 = 8.0
N
1
N
O
Cl
N
H
hH3R K i: unkown
hH4R K i: unkown
human pA2 = 9.2
IC50s > 10 mM for CYP: 1A2, 2C9, 2C19, 2D6 and 3A4
Figure 3. Structure of one of the compounds developed by AstraZeneca.17
Figure 2. Structure and potency profile of 1.13
Table 1
Affinities of compounds 2–22 at human histamine H3 and H4 receptor
Compds
R
Kia (nM)
hH3R
hH4R
Selectivity ratio
hH4R/hH3R
Kib (nM)
Kic (nM)
R,S
2
20
19
23
25
12
18
5
5
5
4
2
4
49
ntd
R
3
12
290 98
24
4
31
ntd
S
R,S
5
21
ntd
6
15
ntd
R
7
4.7 0.9
29
118 38
695 51
426 147
ntd
25
24
22
S
R,S
8
8.7 2.9
R
S
9
19
12
15
4
5
5
19
10
11
12
13
14
42
8.3
13
162 34
123 17
ntd
20
9
R,S
R,S
5.1 1.9
ntd
13
R,S
ntd
30
ntd
(continued on next page)

_
D. Łazewska et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6682–6685
6684
Table 1 (continued)
Compds
R
Kia (nM)
hH3R
hH4R
Selectivity ratio
hH4R/hH3R
Kib (nM)
Kic (nM)
R,S
R
15
16
17
18
19
20
21
22
18
23
18
22
ntd
18
ntd
ntd
4
8
3
5
52
ntd
41
636 150
1460 240
ntd
16
20
S
74
R,S
75
37
779 85
21
R,S
R,S
R
5
91
ntd
28 3e
43 17e
ntd
ntd
S
Ciproxifan
Clobenpropit
Thioperamide
46 4f
612 32g
4.3 0.2g
43 3g
13
1.8
0.7
2.4 0.6f
60 12f
a
[3H]histamine release from synaptosomes of rat cerebral cortex,25 mean sem of at least three independent experiments.
[
b
125I]Iodoproxyfan binding to membranes of CHO-K1 cells expressing the human H3R,26 data from a single experiment with each concentrations tested at least in
triplicate, except for 7 with mean sem of three independent experiments.
c
[3H]Histamine binding to membranes of Sf9 cells expressing the human H4R, co-expressed with G
ai2 and Gb1
c
2 subunits,27,28 mean sem of at least three independent
experiments.
d
Not tested.
e
[
[
125I]Iodoproxyfan binding to membranes of HEK-293 cells expressing the human H3R,16 mean sem of three independent experiments.
f
125I]Iodoproxyfan binding to membranes of CHO-K1 cells expressing the human H3R, data from Ref. 26.
g
[3H]Histamine binding to membranes of HEK-293 cells expressing the human H4R, data from Ref. 16.
O
O
N R
CCl3
Cl
O
O=C=N-R
N
R-NH 2 x HCl
(e)
(d)
O
OH
(f)
N
H
x HCl
R
(c)
(b)
O
N
R-Br
R-OH
O
N
(a)
N
H
2-22
R = alkyl
Scheme 1. General synthesis of carbamates. Reagents and conditions: (a) 48% HBr, H2SO4 (concd); (b) potassium phthalimide, K2CO3, benzyltriethylammonium chloride,
acetone 6 h reflux; (c) phthalimide, DEAD, triphenylphosphine, THF, 3 days rt; (d) (i) NH2–NH2, EtOH, 15 min reflux; (ii) HCl, EtOH; (e) ethyl acetate, catalytic amount of
charcoal, 4–5 h reflux; (f) acetonitrile, 4–5 h reflux.
of these compounds had been previously studied in a functional
test on synaptosomes of rat cortex and showed high histamine
H3R affinity.20,21 Now some of the reported structures were also
tested at the human H4R. Results are collected in Table 1.
The synthetic route for these carbamates is illustrated in
Scheme 1.22 Commercially available or prepared amines were con-
verted to the corresponding isocyanates by the reaction with an
excess of diphosgene. Then, subsequently isocyanates reacted in
acetonitrile with 3-(1H-imidazol-4-yl)-propanol hydrochloride to
furnish the desired carbamates 2–22. Non-commercially available
amines were prepared from the corresponding alcohols as depicted
in Scheme 1. Amines used to synthesize compounds 8, 11 and 12
were obtained from the alkyl bromides via conventional Gabriel
synthesis under phase-transfer conditions.20,23 Subsequently,
N-alkylphthalimides by means of hydrazinolysis gave the desired
amines, isolated as hydrochlorides. Alkyl bromides for 8, 11 and

_
D. Łazewska et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6682–6685
6685
3. Esbenshade, T. A.; Fox, G. B.; Cowart, M. D. Mol. Interventions 2006, 6, 77.
12 were synthesized by standard procedures (48% HBr in concen-
trated H2SO4). Precursor N-alkylphthalimides for carbamates 9,
10, 13, 14 and 22 were prepared via modified Gabriel procedure re-
ported by Mitsunobu.24 These reactions were carried out at room
temperature in absolute THF in the presence of DEAD and
triphenylphosphine.
All compounds reported here revealed high affinities for human
H3R (Ki values from 4.7 to 91 nM). The best acceptable for hH3R is
the methyl substituent in the b position (7 and 11). It looks as if the
ethyl group in this position (19) is also tolerated. However, the lack
of the methyl analogue in the hexyl series did not let us confirm that.
A trend for a stereoselectivity at human H3R was also observed
4. Wijtmans, M.; Leurs, R.; de Esch, I. J. P. Expert Opin. Investig. Drugs 2007, 16, 967.
5. Berlin, M.; Boyce, C. W. Expert Opin. Ther. Patents 2007, 17, 675.
6. Sander, K.; Kottke, T.; Stark, H. Biol. Pharm. Bull. 2008, 31, 2163.
7. Celanire, S.; Lebon, F.; Stark, H. In The Third Histamine H3 Receptor: Selective
Ligands as Potential Therapeutic Agents in CNS Disorders; Vohora, D. S., Ed.; Taylor
& Francis CRC Press: Boca Raton, Fla.; 2009; pp 103–165.
8. Stark, H.; Kathmann, M.; Schlicker, E.; Schunack, W.; Schlegel, B.; Sippl, W.
Mini-Rev. Med. Chem. 2004, 4, 965.
9. Murray, M. Drug Metab. Rev. 1987, 18, 55.
10. Yang, R.; Hey, J.; Aslanian, R.; Rizzo, C. Pharmacology 2002, 66, 128.
11. Berlin, M.; Ting, P. C.; Vaccaro, W. D.; Aslanian, R.; McCormick, K. D.; Lee, J. F.;
Albanese, M. M.; Mutahi, M. W.; Piwinski, J. J.; Shih, N.-Y.; Duguma, L.;
Solomon, D. M.; Zhou, W.; Sher, R.; Favreau, L.; Bryant, M.; Korfmacher, W. A.;
Nardo, C.; West, R. E., Jr.; Anthes, J. C.; Williams, S. M.; Wu, R.-L.; She, S. H.;
Rivelli, M. A.; Corboz, M. R.; Hey, J. A. Bioorg. Med. Chem. Lett. 2006, 16, 989.
12. Chadha, H. S.; Abraham, M. H.; Mitchell, R. C. Bioorg. Med. Chem. Lett. 1994, 4,
2511.
13. Jablonowski, J. A.; Ly, K. S.; Bogenstaetter, M.; Dvorak, C. A.; Boggs, J. D.; Dvorak,
L. K.; Lord, B.; Miller, K. L.; Mazur, C.; Wilson, S. J.; Lovenberg, T. W.; Carruthers,
N. I. Bioorg. Med. Chem. Lett. 2009, 19, 903.
14. Zampeli, E.; Tiligada, E. Br. J. Pharmacol. 2009, 157, 24.
15. de Esch, I. J. P.; Thurmond, R. L. J. A.; Jongejan, A.; Leurs, R. Trends Pharmacol. Sci.
2005, 26, 462.
16. Gbahou, F.; Vincent, L.; Humbert-Claude, M.; Tardivel-Lacombe, J.; Chabret, C.;
Arrang, J. M. Br. J. Pharmacol. 2006, 147, 744.
17. Burns, S.; Hamley, P. Patent WO2005014579, Feb. 17, 2005.
18. Igel, P.; Schneider, E.; Schnell, D.; Elz, S.; Seifert, R.; Buschauer, A. J. Med. Chem.
2009, 52, 2623.
for the chiral
a-branched ligand. Indeed, the R-enantiomers (3, 9,
16 and 21) were slightly more potent than the corresponding
S-enantiomers (4, 10, 17 and 22). In the R-eutomer series, the alkyl
chain consisting of three to five carbons (compare 3, 6 and 9) was
well tolerated by human H3R. A six-carbon chain (compare 3, 6 and
9 with 16) was detrimental for H3R binding and caused about
threefold lost of in vitro affinity. Surprisingly, the seven-carbon
compound 21 had again a better affinity than the six-carbon ana-
logue 16.
In the series of the pentyl derivatives (8–14), the methyl group
was introduced into the different positions (
dimethyl compound (14, and d position) was also prepared. Com-
pounds with the methyl substituent in the b, or d position were
about twice more potent than -branched ones (compare 11, 12
and 13 with 8). Interestingly, the introduction of a second methyl
group in the d position (14) did not influence the affinity when
a
, b,
c
and d) and the
19. Igel, P.; Schnell, D.; Bernhardt, G.; Seifert, R.; Buschauer, A. Chem. Med. Chem.
2009, 4, 225.
a
20. Sasse, A.; Kiec´-Kononowicz, K.; Stark, H.; Motyl, M.; Reidemeister, S.; Ganellin,
C. R.; Ligneau, X.; Schwartz, J.-C.; Schunack, W. J. Med. Chem. 1999, 42, 593.
21. Kiec´-Kononowicz, K.; Wie˛cek, M.; Sasse, A.; Ligneau, X.; Elz, S.; Ganellin, C. R.;
Schwartz, J. C.; Stark, H.; Schunack, W. Pharmazie 2000, 55, 349.
22. Compounds 2–12 and 14–20 were described previously.20,21 Compounds 13,
21 and 22 were prepared as described by Sasse et al.20 The products were
obtained as colorless oils and crystallized as hydrogen maleates in EtOH/Et2O.
c
a
comparing with 8, indicating that
a-substituent determinated
(a)
Compound
13.
Starting
from
4-methylpentan-1-ol;
N-(4-
affinity and prevented the optimal interaction with the H3R.
Comparing the results with those previously obtained in a func-
tional test in rat cerebral cortex,20,21 it is seen that most of the
investigated compounds displayed lower or comparable affinity
at the human H3R. Surprisingly, 7 and 11 are more potent at the
human H3R than at the rat cortex (7: hKi; 4.7 nM, rat Ki: 18 nM;
11: hKi; 8.3 nM, rat Ki: 15 nM).
Some of the compounds (3, 7–9, 11, 12, 16, 17 and 19) were
tested at human H4R.27,28 These studies revealed their moderate
to weak affinities (hKi: 118–1420 nM). The most potent was 7
(hKi: 118 nM), also very active at human H3R (hKi: 4.7 nM). These
chosen compounds (3, 7–9, 11, 12, 16, 17 and 19) had some selec-
tivity for the H3R (from 9 to 25-fold) over the H4R, in some cases
even better than the reference compounds (Table 1).
In summary, we investigated a series of branched 3-(1H-imida-
zol-4-yl)propyl N-alkylcarbamates which were found to be potent
human H3R ligands. Additional pharmacological evaluation of nine
selected compounds showed that these structures, as most imidaz-
ole-containing ligands, displayed also affinity for the H4R. How-
ever, our present and unpublished results indicate that selectivity
for the H3R (high affinity) among imidazole-containing derivatives
over the H4R (weak or lack of affinity) is possible to achieve.
Methylpentyl)phthalimide, yellow oil (yield: 71%); 4-Methylpentanamine
hydrochloride, white solid, Mp 197 °C; yield: 72%; 3-(1-H-Imidazol-4-
yl)propyl N-(4-methylpentyl)carbamate hydrogen maleate, white solid; Mp
81–82 °C; yield: 15%. 1H NMR [DMSO-d6]: d = 8.83 (s, 1H, Im-2-H), 7.37 (s, 1H,
*
Im-5-H), 7.06 (t, J = 5.6 Hz, 1H, CONH ), 6.04 (s, 2H, Mal), 3.96 (t, J = 6.5 Hz, 2H
Imꢀ ꢀ ꢀCH2–O), 2.93 (q, J = 6.4 Hz, 2H, N-CH2), 2.66 (t, J = 7.6 Hz, 2H, Im–CH2),
1.87 (m, 2H, Im–CH2–CH2), 1.51(m, 1H, –CH(CH3)2), 1.38 (m, 2H, –CH2–CH2–
CH(CH3)2), 1.12 (m, 2H, –CH2–CH(CH3)2), 0.84 (d, J = 6.6 Hz, 6H, (CH3)2); IR
(KBr) (cmꢁ1): 1694s (
m
[C@O]); MS m/z (%) 253 ([M+], 8), 109 (½Im—ðCH2Þ3þꢂ,
32), 108 (100), 107 (38), 95 (½Im—ðCH2Þ2þꢂ, 67), 82 (22), 81 (½Im—CH2þꢂ, 35), 80
(11), 54 (16), 41 (18). Anal. Calcd for C13H23N3O2ꢀC4H4O4ꢀ0.5H2O (Mr: 378.30):
C, 53.98; H, 7.46; N, 11.11. Found: C, 54.23; H, 7.10; N, 11.13.(b) Compound 21:
Starting from (R)-(ꢁ)-octan-2-amine (Lancaster). White solid, Mp 105–107 °C;
yield: 30%; [
a
]D: ꢁ2.77 (c 1.0, EtOH); 1H NMR [DMSO-d6]: d = 8.90 (s, 1H, Im-2-
H), 7.40 (s, 1H, Im-5-H), 6.96 (d, J = 8.3 Hz, 1H, CONH), 6.06 (s, 2H, Mal), 3.96 (t,
J = 6.6 Hz, 2H Imꢀ ꢀ ꢀCH2–O), 3.70–3.38 (br s, 1H, N–CH + H2O), 2.69 (t, J = 7.4 Hz,
2H, Im–CH2), 1.90 (t, J = 7.4 Hz, 2H, Im–CH2–CH2), 1.34–1.24 (m, 10H, –(CH2)5),
1.02 (d, J = 6.6 Hz, 3H, –CH–CH3), 0.82 (t, J = 6.3 Hz, 3H, CH2–CH3); IR (KBr)
(cmꢁ1): 1689s
(m
[C@O]); MS m/z (%) 281 ([M+], 4), 113 (46), 109
(½Im—ðCH2Þ3þꢂ, 37), 108 (74), 107 (23), 95 (½Im—ðCH2Þ þꢂ, 70), 82 (24), 81
(½Im—CH2þꢂ, 53), 70 (100), 55 (37), 44 (48).2 Anal. Calcd for
C15H27N3O2ꢀC4H4O4ꢀ0.75H2O (Mr: 410.98): C, 55.53; H, 7.58; N, 10.38. Found:
C, 55.48; H, 7.97; N, 10.22.(c) Compound 22: Starting from (R)-(ꢁ)-octan-2-ol
(Aldrich); N-(S)-(+)-2-octylphthalimide, colorless oil; yield: 79%; [a]D: +29.48
(c 3.0, EtOH); (S)-(+)-octan-2-amine hydrochloride, white solid, Mp 85–86 °C;
yield: 36%; [
]D: ꢁ4.42 (c 1.5, MeOH); 3-(1-H-Imidazol-4-yl)propyl) N-[(S)-(+)-
2-octyl]carbamate hydrogen maleate, white solid; Mp 108–110 °C; yield: 7%;
]D: +2.93 (c 1.0, EtOH); 1H NMR [DMSO-d6]: d = 8.85 (s, 1H, Im-2-H), 7.40 (s,
a
[a
1H, Im-5-H), 6.91 (d, J = 8.3 Hz, 1H, CONH), 6.02 (s, 2H, Mal), 3.93 (t, J = 6.6 Hz,
2H Imꢀ ꢀ ꢀCH2–O), 3.42–3.30 (br s, 1H, N–CH + H2O), 2.65 (t, J = 7.4 Hz, 2H, Im–
CH2), 1.86 (qu, J = 7.4 Hz, 2H, Im–CH2–CH2), 1.31–1.16 (m, 10H, –(CH2)5), 0.98
(d, J = 6.6 Hz, 3H, –CH–CH3), 0.82 (t, J = 6.1 Hz, 3H, CH2–CH3); IR (KBr) (cmꢁ1):
Acknowledgments
1689s (
m
[C@O]); MS m/z (%) 281 ([M+], 12), 109 (½Im—ðCH2Þ3þꢂ, 34), 108 (100),
This work was supported by the Deutscher Akademischer Aust-
auschdienst (D/06/25529), Germany, the Ministry of Scientific Re-
search and Information Technology, Poland DAAD/55/2007
Program and by the ‘LOEWE Lipid Signalling Forschungszentrum’
(LiFF, Frankfurt/Main). D.L., M.W., T.K., L.W., R.S., H.S. and K.K.K.
are affiliated with COST Action BM0806.
107 (22), 95 (½Im—ðCH2Þ2þꢂ, 56), 82 (23), 81 (½Im—CH2þꢂ, 41), 72 (14), 54 (17),
45 (16). Anal. Calcd for C15H27N3O2ꢀC4H4O4ꢀ0.5H2O (Mr: 406.48): C, 56.14; H,
7.94; N, 10.34. Found: C, 56.27; H, 7.89; N, 10.13.
23. Kiec´-Kononowicz, K.; Zejc, A. Polish J. Chem. 1984, 58, 761.
24. Mitsunobu, O. Synthesis 1981, 1.
25. Garbarg, M.; Arrang, J. M.; Rouleau, A.; Ligneau, X.; Trung Tong, M. D.;
Schwartz, J. C.; Ganellin, C. R. J. Pharmacol. Exp. Ther. 1992, 263, 304.
26. Ligneau, X.; Morisset, S.; Tardivel-Lacombe, J.; Gbahou, F.; Ganellin, C. R.; Stark,
H.; Schunack, W.; Schwartz, J.-C.; Arrang, J.-M. Br. J. Pharmacol. 2000, 131, 1247.
27. Schneider, E. H.; Schnell, D.; Papa, D.; Seifert, R. Biochemistry 2009, 48, 1424.
28. Tanrikulu, Y.; Proschak, E.; Werner, T.; Geppert, T.; Todoroff, N.; Klenner, A.;
Kottke, T.; Sander, K.; Schneider, E.; Seifert, R.; Stark, H.; Clark, T.; Schneider, G.
Med. Chem. Med. 2009, 4, 820.
References and notes
1. de Luca, L. Curr. Med. Chem. 2006, 13, 1.
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