Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine

Article abstract of DOI:10.1016/S0960-894X(03)00357-3

Combining the first generation H₁ antihistamine chlorpheniramine (1) with H₃ ligands of the alkylamine type has led to the identification of compound 9d, a dual ligand of both the H₁ and H₃ receptors.

Full text of DOI:10.1016/S0960-894X(03)00357-3

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1959–1961
Identification of a Dual Histamine H1/H3 Receptor Ligand Based
on the H1 Antagonist Chlorpheniramine
Robert Aslanian,* Mwangi wa Mutahi, Neng-Yang Shih, John J. Piwinski, Robert West,
Shirley M. Williams, Susan She, Ren-Long Wu andJohn A. Hey
The Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ07033, USA
Received21 March 2003; revised7 April 2003; accepted9 April 2003
Abstract—Combining the first generation H1 antihistamine chlorpheniramine (1) with H3 ligands of the alkylamine type has led to
the identification of compound 9d, a dual ligand of both the H1 andH receptors.
3
# 2003 Elsevier Science Ltd. All rights reserved.
The histamine H3 receptor is a presynaptic autoreceptor
that controls the release of histamine as well as other
neurotransmitters such as acetylcholine andnor-
epinephrine.1 Most of the interest in the therapeutic use
of H3 receptor antagonists andagonists has been in the
CNS area, including treatment of cognition disorders,
obesity, and sleep-related disorders.2 We, however, have
been interestedin their use for the treatment of allergic
diseases, in particular nasal congestion. We previously
demonstrated that the combination of the selective H1
antagonist chlorpheniramine (1) with the selective H3
antagonist thioperamide prevented congestion in a his-
tamine-driven model of nasal congestion in the cat.3 We
became interested in determining if a dual antagonist of
these receptors could be designed. There is ample pre-
cedent in the histamine literature that supports the con-
cept of dual antagonism in which one of the receptors is
the H1 receptor. These include, among others, dual
PAF/H1 antagonists, NK1/H1 antagonists, H1/H2
antagonists andLTD 4/H1 antagonists.4 Recently,
examples of dual H1/H3 antagonists have also been
reportedalthough these were not originally designedto
be dual antagonists.5 This paper describes our efforts
towards the identification of a dual antagonist of the H1
envisionedthe coupling of H ligands of the alkylamine
3
class (2)7 via the amine moieties that are common to
both (Fig. 1). Optional linking groups on either side of
the amine moiety provided further opportunity to
introduce diversity into the molecules.
Figure 1.
The preparations of the putative dual H1/H3 ligands are
given in the following Schemes. Analogues in which
n=2 or 4 possessing either an amide linker or a straight
alkyl chain were preparedas shown in Schemes 1 and2
(exemplifiedfor n=4). Wittig olefination of the known
ketone 4 gave a 1:1 mixture of olefin isomers 5.
Although these couldbe separatedvia column chroma-
tography, the mixture was reduced directly to give the
ester 6. The ester 6 was convertedto the amides 7 by
treatment with the Weinreb reagent8 formedfrom the
alkylamine7 andMe 3Al. Removal of the triphe-
nylmethyl (Tr) protecting group on the imidazole ring
andH
antagonist chlorpheniramine.
receptors basedon the first-generation H
1
3
Chlorpheniramine (1) is a potent antagonist of the
human H1 receptor (Ki=2 nM).6 Our approach for the
design of dual H1/H3 ligands based on chlorpheniramine
*Corresponding author. Tel.: +1-908-7403514; fax: +1-908-7407305;
e-mail: robert.aslanian@spcorp.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00357-3

1960
R. Aslanian et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1959–1961
gave the amide analogues 8 (R=H). Alternatively, the
amide nitrogen was alkylated followed by deprotection
of the imidazole ring to give 8 (R=CH3). Reduction of
the amide 7 followedby deprotection gave the amine
analogues 9. In an analogous manner, amide 10 and
amine 11 were prepared.
The three-carbon homologues were preparedstarting
from the known ester 13 (Scheme 2).9 Horner–Wads-
worth-Emmons olefination of 5 followedby reduction
of the nitrile anddouble bondgave amine
12. This
amine was coupledwith ester 13 using Weinreb chem-
istry to give amide 14. Further manipulation in the same
manner as that usedto produce analogues in which
n=2 or 4 gave the desired targets 15 (n=2) and 16
(n=2).
The synthesis of urea andamidine linkedanalogues is
given in Schemes 3 and4 . Amine 12 was convertedto
the isocyanate 17 andthen coupledwith 1-trityl-4-(4-
aminobutyl)imidazole to give the urea analogue 18
(n=4) after deprotection.
The amidine 20 (n=2) was formedby reaction of the
nitrile 19 with the Weinreb amide formed from 1-tri-
phenylmethyl histamine andMe 3Al. Deprotection of
the imidazole ring gave the target. In a similar manner,
amidine 21 (n=3) was preparedfrom amine 12 andtri-
tyl-protected3-[4(5)-imidazolyl]butyronitrile.
Compounds were evaluated for H3 binding affinity
using guinea pig brain membranes as described by
Korte et. al.10 andfor H binding affinity using the
1
Scheme 1. (a) Ph3PCH2CO2CH3Br, NaH, THF, 92%; (b) Mg,
MeOH, 45%; (c) Me3Al, aminoalkyl imidazole, toluene, 77%; (d)
NaH, MeI, THF, 67% (R=CH3); (e) 1N HCl, EtOH, 95% (7 to 8),
procedure of Tran.11 These data are presented in Table
1.
.
100% (7 to 9); (f) BH3 Me2S, THF, 100%.
Examination of these data indicates that it is easier to
maintain H3 binding affinity than H1 binding affinity in
this series. For example, both neutral linkers like amides
Scheme 3. (a) Triphosgene, pyridine, 100%; (b) aminoalkylimidazole,
pyridine, 50%; (c) 1N HCl, EtOH, 90%.
Scheme 2. (a) Ph3PCH2CNBr, NaH, THF, 90%; (b) NaBH4, i-PrOH,
reflux, 78%; (c) LiAlH4, Et2O, reflux, 36%; (d) 12, Me3Al, toluene,
80%; (e) NaH, MeI, THF, 94% (for R=CH3); (f) 1N HCl, EtOH,
quantitative; (g) LiAlH4, THF, 19%.
Scheme 4. (a) Ph3PCH2CNBr, NaH, THF, 90%; (b) NaBH4, 2-pro-
panol, reflux, 78%; (c) Me3Al, 1-triphenylmethyl histamine, toluene;
(d) 1N HCl, EtOH, 68% for steps c and d.

R. Aslanian et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1959–1961
1961
Table 1. H1 andH 3 receptor binding affinity
receptors to determine if dual affinity for the H1 andH 3
receptors by a single chemical entity is possible. This led
to the identification of compounds that in general display
Example No.
n
R
Ki (H1, nM)a
Ki (H3, nM)a
very goodaffinity for the H receptor, but much lower
3
8a
8b
8c
8d
9a
9b
9c
9d
9e
10
11
15a
15b
16a
16b
18
2
4
4
2
2
4
5
4
5
—
—
2
2
2
2
4
2
3
H
H
CH3
CH3
H
H
H
CH3
CH3
H
H
H
CH3
H
CH3
—
N.A.b
N.A.
N.A.
N.A.
600
254
39
7
16
1
7
affinity for the H1 receptor. However, compound 9d,
incorporating a tertiary amine as the linker, displays very
goodbinding affinity for both the H 1 andH 3 receptors (7
and15 nM, respectively). Compounds such as this may be
useful additions to current therapies for the treatment of
allergies andnasal congestion.
1
56
10
33
15
50
1
6
N.A.
N.A.
N.A.
N.A.
N.A.
10
920
N.A.
201
4
References and Notes
510
260
240
120
23
8
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. Leurs, R.; Blandina, P.; Tedford, C.; Timmerman, H.
Trends Pharmacol. Sci. 1998, 19, 177.
20
21
—
—
29
aBinding Ki values are the average of at least two independent deter-
minations. The average Ki value for thioperamide in the H3 assay is
7.3Æ0.7 nM; the average Ki value for chlorpheniramine in the H1
binding assay is 2.1Æ0.2 nM.
3. McLeod, R. L.; Mingo, G. G.; Herczku, C.; DeGennaro-
Culver, F.; Kreutner, W.; Egan, R. W.; Hey, J. A. Am. J.
Rhinol. 1999, 13, 391.
4. (a) Billah, M. M.; Chapman, R. W.; Egan, R. W.; Gilchr-
est, H.; Piwinski, J. J.; Sherwood, J.; Siegel, M. I.; West, R. E.;
Kreutner, W. J. Pharmacol. Exp. Ther. 1990, 252, 1090. (b)
Maynard, G. D.; Bratton, L. D.; Kane, J. M.; Burkholder,
T. P.; Santiago, B.; Stewart, K. T.; Kudlacz, E. M.; Shatzer,
S. A.; Knippenberg, R. W.; Farrell, A. M.; Logan, D. E.
Bioorg. Med. Chem. Lett. 1997, 7, 2819. (c) Schulze, F. R.;
Buschauer, A.; Schunack, W. Eur. J. Pharm. Sci. 1998, 6, 177.
(d) Zhang, M. Q.; van de Stolpe, A.; Zuiderveld, O. P.; Tim-
merman, H. Eur. J. Med. Chem. 1997, 32, 95.
5. (a) Huls, A.; Purand, K.; Stark, H.; Ligneau, X.; Arrang,
J.-M.; Schwartz, J.-C.; Schunack, W. Bioorg. Med. Chem.
Lett. 1996, 6, 2013. (b) Walczynski, K.; Guryn, R.; Zuiderveld,
O. P.; Timmerman, H. Il Farmaco 1999, 54, 684.
6. Anthes, J. A.; Gilchrest, H.; Richard, C.; Eckel, S.; Hesk,
D.; West, R. E.; Williams, S. M.; Greenfeder, S.; Billah, M.;
Kreutner, W.; Egan, R. W. Eur. J. Pharmacol. 2002, 449, 229.
7. Vollinga, R. C.; Menge, W. M. P. B.; Leurs, R.; Timmer-
man, H. J. Med. Chem. 1995, 38, 266.
bN.A., Less than 50% inhibition when screenedat 1 mg/mL.13
andureas (Examples 8a–d and 18) as well as analogues
with a basic linker like an amine or amidine (Examples
9b,c, 20 and 21) display excellent affinity for the H3
receptor. Interestingly, the amides appear to display
higher receptor affinity then the corresponding amines
(8a–d vs 9a–d). Furthermore, binding affinity for the H3
receptor is sensitive to the carbon chain length between
the imidazole ring and the amine linker. The four car-
bon chain analogues are generally superior to the two,
three or five carbon chains. This result differs somewhat
from Timmerman’s original work in a structurally simi-
lar alkylamine series where H3 affinity peakedwith the
five-carbon linker.7
8. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1997, 48, 4171.
9. Browne, L. J.; Gude, C.; Rodriguez, H.; Steele, R. E. J.
Med. Chem. 1991, 34, 725.
In contrast to the generally goodH binding affinity of
3
this series, H1 binding affinity is much more sensitive to
the nature of the substrate. None of the compounds
which incorporate a neutral linker (i.e., amide or urea)
display significant H1 binding affinity. However, incor-
porating a basic amine into the linking group restores
H1 binding affinity, which is optimum, when the linker
is a tertiary amine (Examples 9d, 9e and 16b). This
result is consistent with the known structural require-
ments for a first generation H1 ligand, namely that a
basic amine, capable of interacting with the aspartic
acidresidue in transmembrane 3, be present.12
10. Korte, A. K.; Myers, J.; Shih, N.-Y.; Egan, R. W.; Clark,
M. A. Biochem. Biophys. Res. Commun. 1990, 168, 979. The
source of the receptors in these experiments was guinea pig
brain. [3H]Na-methyl histamine was used as the radioligand.
11. Tran, V. T.; Chang, R. S. L.; Snyder, S. Proc. Natl. Acad.
Sci. U.S.A. 1978, 75, 6290 The source of the receptors in these
experiments was male Sprague–Dawley rat brain. [3H]Pyr-
ilamine was used as the radioligand.
12. Wieland, K.; Ter Laak, A.; Smit, M. J.; Kuhne, R.; Tim-
merman, H.; Leurs, R. J. Biol. Chem. 1999, 274, 29994.
13. Compounds are screened at a concentration of 1 mg/mL
andthose edmonstrating greater than 50% inhibition are
submittedfor a Ki determination.
In conclusion, a series of compounds has been prepared
that combine known pharmacophores of the H1 andH 3