Azole derivatives as histamine H3 receptor antagonists, Part I: Thiazol-2-yl ethers

Article abstract of DOI:10.1016/j.bmcl.2010.07.098

Most human histamine H₃ receptor (hH₃R) antagonists follow a general structural blueprint, containing a basic moiety linked by a spacer to a substituted core element. In this investigation the acceptance of thiazol-2-yl ether moieties in the core region is proved with some ether derivatives showing hH₃R binding affinities in the nanomolar concentration range. A diversity of structural motifs is used as substituents to enhance the in vitro hH₃R binding affinity.

Full text of DOI:10.1016/j.bmcl.2010.07.098

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5879–5882
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Azole derivatives as histamine H3 receptor antagonists, Part I:
Thiazol-2-yl ethers
M. Walter a, Y. von Coburg a, K. Isensee a, K. Sander a, X. Ligneau b, J.-C. Camelin b, J.-C. Schwartz b, H. Stark a,
*
a Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biocenter, ZAFES/LiFF/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
b Bioprojet-Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint Grégoire Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Most human histamine H3 receptor (hH3R) antagonists follow a general structural blueprint, containing a
basic moiety linked by a spacer to a substituted core element. In this investigation the acceptance of thia-
zol-2-yl ether moieties in the core region is proved with some ether derivatives showing hH3R binding
affinities in the nanomolar concentration range. A diversity of structural motifs is used as substituents
to enhance the in vitro hH3R binding affinity.
Received 23 June 2010
Revised 23 July 2010
Accepted 25 July 2010
Available online 1 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
GPCR
Histamine
H3
Pharmacophore
The human histamine H3 receptor (hH3R) is one of four known G
protein-coupled histamine receptors (hH1R–hH4R).1 hH3R is acting
as autoreceptor on synthesis and liberation of histamine. As het-
eroreceptor it modulates the release of several other neurotrans-
mitters.2 Due to a distinct expression pattern in the central
nervous system (CNS) and the resulting involvement in several
neuronal functions the hH3R is an attractive target for the treat-
ment of CNS disorders.3
thiazole ring aiming at the evaluation of the variability of the cen-
tral core group. The acceptance of polar heterocycles replacing the
Western part
Eastern part
Polar group
Since the identification of the H3R in 19834 and its cloning in
19995 many H3R ligands were developed by academia and indus-
try, which led to extensive knowledge of antagonist/inverse ago-
nist pharmacophores and ligand–receptor interactions. Among
the diversity of structural classes, almost all compounds follow a
general hH3R antagonist blueprint, which contains a basic moiety,
mostly a tertiary amine, linked by a spacer to a central core, that is,
substituted by a variety of structural elements providing different
physicochemical properties (Fig. 1).6 Several pharmacophore mod-
els7 indicated the usefulness of an aromatic, lipophilic element as
central core moiety. Hence, a phenyl ring is used in numerous po-
tent hH3R ligands.8
The identification of new lead structures required differentia-
tion from these frequently approached scaffolds. Here, we focused
on the central core element. In earlier studies, the benzthiazol-2-yl
ether derivative FUB-658 and others were identified as moderately
acting H3R inverse agonist (ED50 value of 18 7 mg/kg p.o.).9,10 We
used this lead compound as a starting point for modification of the
1st
Basic
moiety
2nd Basic moiety
Lipophilic residue
Acidic moiety
Central
core
Spacer
Figure 1. Expanded hH3R antagonist blueprint.6
O
N
N
N
O
N
N
N
N
S
S
N
N
Abbott
WO 2009085945A112
Glaxo Group Limited
11
WO 2006097691
O
CH3
N
F
N
N
S
H3C
N
N
O
N
N
S
N
O
UCB Pharma13
Schering-Plough14
* Corresponding author. Fax: +49 69 79829258.
E-mail address: h.stark@pharmchem.uni-frankfurt.de (H. Stark).
Figure 2. Representative thiazole-containing hH3R antagonists.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.098

5880
M. Walter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5879–5882
commonly used phenyl residue should be proven. Several other
thiazole-containing series published in patents and original litera-
ture were regarded as proof of concept (Fig. 2).11–14 However, H3R
binding properties still had to be improved.
Enlargement of the thiazole motif in the eastern part of the mol-
ecule by different substituents such as lipophilic residues, basic
moieties and/or carbonyl groups should enhance the knowledge
about structure–activity relationships (SAR) of thiazole-containing
ligands, leading to new affine hH3R antagonists/inverse agonists.
The western part of the molecule, represented by an 1-(3-oxypro-
pyl)amine element, was kept constant (Fig. 3).
hydrobromide.17 Alternatively, the substitutive de-amination with
copper(II)bromide and tert-butyl nitrite was performed.18
An ether synthesis displayed the last step of the reaction. First
the precursor alcohols 3-(piperidine-1-yl)- (A) and 3-dimethylami-
nopropan-1-ol (B), prepared according to literature methods,19
were converted into the respective alcoholates by reaction with so-
dium hydride. The formation of compounds 1–15 occurred by add-
ing the appropriate 2-bromothiazole derivatives 1c–15c.
The final compounds 1–15 were tested with regard to their
in vitro hH3R binding affinity in an [125I]iodoproxyfan binding as-
say (Table 1).20
Synthesis of the thiazole ligands 1–15 is shown in Scheme 1.
The varying substitution pattern on positions 4 and 5 of the hetero-
cycle required different ways of preparation. The 2-aminothiazole
intermediates were obtained by Hantzsch-thiazole synthesis, a
Introduction of the thiazol-2-yl ethers as core element with a
diversity of substituents in 4- and 5-positions of the heterocycle
reaction of
a
-bromoketones with thiourea.15 1-(3-(Piperidine-1-
Table 1
yl)propyl)piperidine-4-one 8a was prepared by N-alkylation of
piperidone with 1-(3-chloropropyl)piperidine under basic condi-
tions. The commercially available ketones 1a–7a and 9a–15a as
well as precursor 8a were brominated either in chloroform or in
glacial acetic acid under addition of hydrobromide.16 By adding
thiourea the ring closure took place in ethanol. 2-Aminothiazoles
1b–15b were further functionalized in 2-position to enable the
coupling of piperidine- or the (dimethylamino)propyl building
block. They were converted into 2-bromothiazole derivatives 1c–
15c by generating a diazonium salt and subsequent reaction with
In vitro binding affinities of azole derivatives 1–15 at hH3R
R1
N
O
N
R2
R3
S
R4
Compd
R1R2N
CH3
R3
R4
Ki hH3Ra (nM)
CH3
N
1
257 76
N
H3C
CH3
N
2
3
>1000
>1000
H3C
H3C
H3C
CH3
N
O
Western part
Core
Eastern part
CH3
N
O
N
N
4
153 48
N
O
S
CH3
5
24
14
3
2
N
Lipophilic residue
2nd Basic moiety
Carbonyl group
N
CH3
6
N
N
N
N
N
N
N
N
N
N
N
O
N
S
7
261 62
N
N
8
20
1
Figure 3. Lead structure modification and scaffold development.
9
357 54
344 15
93 16
a
N
N
NH
Cl
N
O
10
11
12
13
O
O
O
8a
Br
R3
R4
R3
R4
R3
R4
N
S
N
d
b, c
Br
H2N
CH3
41
6
S
1a-15a
1b-15b
1c-15c
11.2 2.1
155 34
R1
N
R1
N
e
O
N
O
R3
OH
R2
R2
14
CH3
CH3
S
A and B
1-15
R4
O
N
Scheme 1. Synthesis of thiazole ligands 1–15. For definition of R1–4, see Table 1.
Reagents and conditions: (a) K2CO3, KI, acetone, reflux, 72 h, 79%. (b) For
compounds 2–4, 8–15: Br2, chloroform, 0 °C ? rt/50 °C, respectively, 1–3 h,
66–100%; for compounds 1, 5–7: Br2, HBr, glacial acetic acid, 0 °C ? rt, 15 min,
100%. (c) Thiourea, ethanol, 90 °C, 1.5–3 h, 8–92%. (d) For compounds 2–4, 8–15:
CuBr2, tert-butyl nitrite, acetonitrile, 0 °C ? rt, 4–18 h, 29–75%; compounds 1, 5–7:
NaNO2, HBr, À30 °C, 1 h ? 4 °C, 18 h, 29–37%. (e) (i) NaH, THF, 40 °C, 30 min–3 h;
(ii) 2-bromothiazole derivatives 1c–15c, 40–90 °C, 3–18 h, 5–66%.
15
>1000
Pitolisant (Tiprolisant, BF2.649)b
2.7 0.5
a
[
125I]Iodoproxyfan (Kd = 44 6 pM) competitive binding assay on HEK-293 cells
stably expressing hH3R; values as means SD of one experiment performed at least
in triplicates
b
Ref. 20c.

M. Walter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5879–5882
5881
led to pronounced differences in hH3R binding. Affinities vary from
the low nanomolar concentration range to the complete loss of
receptor binding.
In compounds 1–4 the first basic moiety in the western part of
the structural blueprint is represented by a dimethylamino func-
tion. These derivatives showed only weak binding behaviour with
Ki values ranging from 150 to >1000 nM. Hence, we replaced the
(dimethylamino)alkyl group by an alkylated piperidine.
Introduction of an additional basic moiety often leads to im-
proved receptor binding caused by an additional beneficial interac-
tion with the receptor’s binding pocket (Glu206).7 This effect can
be noticed in compounds 5 and 6, which both showed a compara-
ble affinity in the nanomolar concentration range (Ki values of
24 nM and 14 nM, respectively). The analogue compound of li-
gands 5 and 6, the benzyl amine 7, showed decreased receptor
binding (Ki value of 261 nM). Possibly, the phenyl ring sterically
hindered the interaction of the second basic moiety with the ligand
binding site. The incorporation of a third basic moiety (ligand 8) of-
fered no further enhancement of affinity compared to that of com-
pounds 5 and 6. Receptor binding remained in the low nanomolar
concentration range (Ki value of 20 nM). Dibasic compounds show
a certain potential to accumulate centrally. As a consequence they
might induce unwanted side effects,21 on which one must pay
attention in further developments.
receptor binding than its substituents. SAR of the presented ligands
indicated additional basic moieties (compounds 5, 6, 8) and
enlargement of the molecule by lipophilic residues (compound
13, ST-1025) as major reason for high affine hH3R antagonists.
We proved the acceptance of polar moieties and therefore the var-
iability in the core region of the hH3R antagonist/inverse agonist
blueprint. Research concerning this variability by further optimisa-
tion of the thiazole derivatives and the incorporation of other het-
erocycles are awaited for following investigations.
Acknowledgments
This work was partially supported by the COST action BM0806
‘Recent Advances in Histamine Receptor H4R Research’, the Else
Kröner-Fresenius-Stiftung, and the Hesse LOEWE projects LiFF
and NeFF.
Supplementary data
Supplementary data (analytical data of parent compounds)
associated with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2010.07.098.
References and notes
The exchange of the amino group in the fused thiazole structure
either by non-polar methylene (compound 9) or polar ether func-
tions (compound 10) revealed the importance of additional basic
moieties for receptor binding. Both modifications led to decreased
affinities (9 and 10 vs 5) with Ki values of about 350 nM.
1. Hill, S. J.; Ganellin, C. R.; Timmerman, H.; Schwartz, J. C.; Shankley, N. P.; Young,
J. M.; Schunack, W.; Levi, R.; Haas, H. L. Pharmacol. Rev. 1997, 49, 253.
2. Sander, K.; Kottke, T.; Stark, H. Biol. Pharm. Bull. 2008, 31, 2163.
3. (a) Leurs, R.; Bakker, R. A.; Timmerman, H.; de Esch, I. J. P. Nat. Rev. Drug Discov.
2005, 4, 107; (b) Esbenshade, T. A.; Browman, K. E.; Bitner, R. S.; Strakhova, M.;
Cowart, M. D.; Brioni, J. D.; Br. J. Pharmacol. 2008, 154, 1166.
The 5-bromo-4-phenyl derivative 11 offered a moderate bind-
ing behaviour (Ki value of 93 nM). Exchange of bromo to methyl
substituent in compound 12 led to a slight improvement in recep-
tor binding (Ki value of 41 nM), whereas the addition of a second
phenyl residue in compound 13 evoked high affinity at the hH3R
(Ki value of 11.2 nM). Obviously, affinity is influenced by lipophil-
icity, steric as well as electronic effects. Whereas electron-with-
drawing properties showed detrimental effects on binding
behaviour (11 vs 12 and 13), increased lipophilicity is advanta-
geous (12 < 13). Positive effects on hH3R affinity of bulky/lipophilic
residues as substituents in the eastern part of the molecule have
previously been reported in other classes.22
Incorporation of a carbonyl function next to the heterocycle led
to reduced receptor binding. Compound 14 showed an affinity in
the submicromolar concentration range (Ki value of 155 nM). The
conformationally constrained derivative 15 completely lost hH3R
affinity. Due to the sterically modified constitution of the carbonyl
moiety as hydrogen bond acceptor, electronic properties were lar-
gely modified (14 vs 15), which may cause impairment of affinity.
In comparison to the dimethylamino motif the 1-(3-oxypro-
pyl)piperidine element in the western part of the molecule, which
was kept constant in compounds 5–15, offered higher receptor
binding. Only hH3R affinity of compound 4 with a Ki value of
153 nM was increased in contrast to the inactive piperidine ana-
logue 15. The affinity of compound 4 was even comparable to
the non-constrained carbonyl analogue 14. These opposing effects
of the dimethylamino compounds (1–3 vs 4) clearly demonstrated
the limitations of SAR within our series of thiazole-containing
compounds.
4. Arrang, J. M.; Garbarg, M.; Schwartz, J. C. Nature 1983, 302, 832.
5. Lovenberg, T. W.; Roland, B. L.; Wilson, S. J.; Jiang, X.; Pyati, J.; Hurvar, A.;
Jackson, M. R.; Erlander, M. G. Mol. Pharmacol. 1999, 55, 1101.
6. (a) Célanire, S.; Wijtmans, M.; Talaga, P.; Leurs, R.; de Esch, I. J. P. Drug Discovery
Today 2005, 10, 1613; (b) Célanire, S.; Lebon, F.; Stark, H. In The Third Histamine
Receptor; Vohora, D., Ed.; CRC Press, Taylor and Francis LLC: New York, 2009; pp
103–165; (c) Gemkow, M. J.; Davenport, A. J.; Harich, S.; Ellenbroek, B. A.;
Cesura, A.; Hallett, D. Drug Discovery Today 2009, 14, 509; (d) Sander, K.; von
Coburg, Y.; Camelin, J.-C.; Ligneau, X.; Rau, O.; Schubert-Zsilavecz, M.;
Schwartz, J.-C.; Stark, H. Bioorg. Med. Chem. Lett. 2010, 20, 1581.
7. (a) Axe, F. U.; Bembenek, S. D.; Szalma, S. J. Mol. Graphhics Modell. 2006, 24, 456;
(b) Schlegel, B.; Laggner, C.; Meier, R.; Langer, T.; Schnell, D.; Seifert, R.; Stark,
H.; Holtje, H. D.; Sippl, W. J. Comput. Aided Mol. Des. 2007, 21, 437; (c) Roche, O.;
Nettekoven, M.; Vifian, W.; Rodriguez Sarmiento, R. M. Bioorg. Med. Chem. Lett.
2008, 18, 4377.
8. (a) Ganellin, C. R.; Leurquin, F.; Piripitsi, A.; Arrang, J. M.; Garbarg, M.; Ligneau,
X.; Stark, H.; Schunack, W.; Schwartz, J. C. In Histamine Research in the New
Millennium; Watanabe, T., Timmerman, H., Yanai, K., Eds.; Elsevier Science:
Amsterdam, 2001; pp 25–31; (b) Berlin, M.; Boyce, C. W. Expert Opin. Ther.
Patents 2007, 17, 675; (c) Wijtmans, M.; Leurs, R.; de Esch, I. Expert Opin.
Investig. Drugs 2007, 16, 967; (d) Raddatz, R.; Tao, M.; Hudkins, R. L. Curr. Top.
Med. Chem. 2010, 10, 153.
9. Schwartz, J.-C.; Arrang, J.-M.; Garbarg, M.; Lecomte, J.-M.; Ligneau, X.;
Schunack, W. G.; Stark, H.; Ganellin, C. R.; Leurquin, F.; Elz, S.; Patent
EP0982300 A2, 2000.
10. Bordi, F.; Mor, M.; Morini, G.; Plazzi, P. V.; Silva, C.; Vitali, T.; Caretta, A.
Farmaco 1994, 49, 153.
11. Bailey, N; Pickering, P. L.; Wilson, D. M. PCT Int. Appl. WO 2006097691, 2006.
12. Black, L. A.; Cowart, M. D.; Gfesser, G. A.; Wakefield, B. D.; Altenbach, R. J.; Liu,
H.; Zhao, C.; Hsieh, G. C. PCT Int. Appl. WO 2009085945 A1, 2009.
13. Denonne, F.; Atienzar, F.; Célanire, S.; Christophe, B.; Delannois, F.; Delaunoy,
C.; Delporte, M.-L.; Durieu, V.; Gillard, M.; Lallemand, B.; Lamberty, Y.; Lorent,
G.; Vanbellinghen, A.; Van houtvin, N.; Verbois, V.; Provins, L. ChemMedChem
2010, 5, 206.
14. Rao, A. U.; Palani, A.; Chen, X.; Huang, Y.; Aslanian, R. G.; West, R. E., Jr.;
Williams, S. M.; Wu, R.-L.; Hwa, J.; Sondey, C.; Lachowicz, J. Bioorg. Med. Chem.
Lett. 2009, 19, 6176.
15. (a) Hantzsch, A.; Traumann, V. Chem. Ber. 1888, 21, 938; (b) Wiley, R. H.;
England, D. C.; Behr, L. C. Org. React. 1951, 6, 367.
16. Gadad, A. K.; Palkar, M. B.; Anand, K.; Noolvi, M. N.; Boreddy, T. S.; Wagwade, J.
Bioorg. Med. Chem. 2008, 16, 276.
We successfully introduced polar thiazo-2-yl ether moieties in
the central core of the hH3R antagonist structural blueprint. The
different substituents on positions 4 and 5 of the heterocycle led
to a great variation in hH3R affinity ranging from nanomolar bind-
ing strength to completely loss of affinity. Obviously, in our series
of thiazoles the heterocycle seemed to have a lower impact on
17. Butler, R. N. Chem. Rev. 1975, 75, 241.
18. Doyle, M. P.; Siegfried, B.; Dellaria, J. F., Jr. J. Org. Chem. 1977, 42, 2426.
19. Isensee, K.; Amon, M.; Garlapati, A.; Ligneau, X.; Camelin, J.-C.; Capet, M.;
Schwartz, J.-C.; Stark, H. Bioorg. Med. Chem. Lett. 2009, 19, 2172.

5882
M. Walter et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5879–5882
20. (a) Ligneau, X.; Garbarg, M.; Vizuete, M. L.; Diaz, J.; Purand, K.; Stark, H.;
Schunack, W.; Schwartz, J. C. J. Pharmacol. Exp. Ther. 1994, 271, 452; (b) 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; (c)
Ligneau, X.; Perrin, D.; Landais, L.; Camelin, J.; Calmels, T. P.; Berrebi-Bertrand,
I.; Lecomte, J. M.; Parmentier, R.; Anaclet, C.; Lin, J. S.; Bertaina-Anglade, V.; La
Rochelle, C. D.; d’Aniello, F.; Rouleau, A.; Gbahou, F.; Arrang, J. M.; Ganellin, C.
R.; Stark, H.; Schunack, W.; Schwartz, J.-C. J. Pharmacol. Exp. Ther. 2007, 320,
365.
21. Hancock, A. A. Biochem. Pharmacol. 2006, 71, 1103.
22. von Coburg, Y.; Kottke, T.; Weizel, L.; Ligneau, X.; Stark, H. Bioorg. Med. Chem.
Lett. 2009, 19, 538.