Conformationally-restricted ligands for the histamine H1 receptor

Article abstract of DOI:10.1016/S0960-894X(00)00199-2

Potent H₁-antagonistic activity in a series of novel indeno[2,1-c]pyridines and their 4-arylpiperidinol precursors is reported; one compound shows an in vitro activity four times that of the standard mepyramine that it was screened against. Their failure to translate this protection to in vivo tests is discussed. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00199-2

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1277±1279
Conformationally-restricted Ligands for the Histamine
H1 Receptor
Christopher Upton, a,* Richard H. Osborne b and Mohammad Ja€ar a
aDepartment of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK
bDepartment of Biological Sciences, University of the West of England, Bristol BS16 1QY, UK
Received 11 February 2000; accepted 31 March 2000
AbstractÐPotent H1-antagonistic activity in a series of novel indeno[2,1-c]pyridines and their 4-arylpiperidinol precursors is
reported; one compound shows an in vitro activity four times that of the standard mepyramine that it was screened against. Their
failure to translate this protection to in vivo tests is discussed. # 2000 Elsevier Science Ltd. All rights reserved.
As part of a continuing project concerned with probing
the H1-histamine receptor,1 8 we report the novel biolo-
gical activity of a series of ligands at this site. Relatively
little biological work has been reported for these synthe-
tically-accessible piperidines and tricyclic derivatives.9 11
Earlier work describing the preparation and biology of
analogous compounds12,13 suggested that the anti-
histaminic activity in such tricyclic compounds resided in
the 2,3,4,9-tetrahydro derivatives (19±22) and no data
were reported for their precursor piperidines and 2,3-
dihydroindenopyridines (1±14) respectively. We describe
our biological results for these compounds below.
each dose group and the number of mice to survive
more than 240 min was recorded. Results are displayed
in Table 1.
Preliminary results from experiments designed to exam-
ine antagonistic activity at the H1-histamine receptor in
guinea pig ileum showed that piperidines 1 and 2 were
e€ective in this screen with IC50 values of 26 and 23 nM,
respectively. These ®gures were comparable with those
for the clinically-established phenindamine (36 nM, deter-
mined at the same time) and led us to screen a range of
piperidines (1±11) in vivo, using the 48/80 challenge test.
All 11 compounds, including 1 and 2 which had showed in
vitro activity, were not capable of protecting mice against a
lethal dose of 48/80 in this screen. The calculated lipo-
philicity16 for piperidines 3±11, were between 10 and
100 times that of 1 (log P 2.6) and may have a€ected the
pharmacokinetics of distribution of the drug with
respect to its site of action. Alternatively, these 4-aryl-4-
hydroxypiperidines have been shown to be metaboli-
cally labile19,20 and this susceptibility may have a role in
the failure to transfer this in vitro activity to the whole
animal.
For in vitro activity, dose±response curves were con-
structed for histamine in the absence and presence of
mepyramine, phenindamine and test substances. The
tissue was allowed to equilibrate with each concentration
of antagonist for 30 min prior to retesting the agonist
action of histamine.14
Dose±response curves were plotted as a percentage of the
histamine maximum response in the absence of antago-
nists against log10 of the molar concentration of hista-
mine; selected IC50 values calculated from these data are
recorded in Table 1. For in vivo activity compounds
tested were administered at doses of 40 or 10 mg/kg, s.c.
before challenging the animal with the potent, histamine-
releasing oligomer 48/80 (0.5 mg/kg, iv).15 A successful
outcome in these tests is protection against lethal, his-
tamine-induced anaphylaxis. Two mice were assigned to
Cyclisation of the appropriate piperidines in the pre-
sence of 48% w/v HBr produces the tricyclic nucleus of
the dienes5 of which 3 were screened, 12±14, (Scheme 1
and Table 1) as they have not been scrutinised for anti-
histaminic activity. The diene 13 has about one tenth of
the activity of the clinical-used drug mepyramine but
the N-ethyl analogue 14 appeared not to act in a similar
manner as it would not produce an inhibition of 50%
and the shape of the dose±response curve suggested that
a non-competitive mode of action may be in evidence.
*Corresponding author. Fax: +44-1225-826114;
e-mail: c.upton@bath.ac.uk
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00199-2

1278
C. Upton et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1277±1279
Table 1. In vitro and in vivo antihistaminic activity of the tricyclic nuclei 12±22
Compounda
12
13
14
15
16
17
18
19
20
21
22
R1
R2
IC50
48/80d
Log Pe
H
H
53
1/2, 0/2
4.41
Me
H
220
0/2, 0/2
4.94
Et
H
Me
H
28
2/2, 1/2
5.23
Et
H
Ð
2/2, 1/2
5.76
PhCH2
H
10.8
0/2, 0/2
7.03
PhEt
H
Ð
1/2, 0/2
7.43
Me
7,40-Et
Ð
0/2, 0/2
Ð
Et
H
17
1/2, 0/2
4.92
PhCH2
H
470
0/2, 0/2
6.02
PhEt
H
Ð
0/2, 0/2
6.59
b
NIc
Ð
Ð
aSee Scheme 1 for structures.
bThe number of determinations made for each compound was 5 or 6, the clinically-established mepyramine and phenindamine were also included in
these determinations and had IC50 of 34 and 36 nM resp., concentrations of test substances are cited similarly.
cNI: did not cause 50% inhibition.
dDetermined at doses of 40 and 10 mg/kg, resp. in the 48/80 challenge, numbers given are mice surviving for more that 240 min; under these con-
ditions the ED50 for mepyramine was <2.5 mg/kg.
eDerived as described in ref 16, errors were between Æ0.37 and Æ0.39.
Scheme 1. Reagents: (i) 48% w/v HBr; (ii) H2, 10% Pd on C, RT; (iii) H2, 5% Pt on C, 80 psi, 75 ꢀC, 20 h. 3±8: R1=benzyl, phenethyl, cyclopropyl,
butyl, hexyl and cyclohexylmethyl, resp.: R2=H. 9±11: R1=Me, R2=4-Cl, 4-Me and 3-Br resp.
Some H1-antagonism was endowed by the N-dealky-
lated diene 12 in the in vivo tests, ED50 40 mg/kg.
manifest themselves in the in vivo 48/80 challenge: the
only successful activities from this screen of tricyclic
molecules were for 15 and 16, at the higher dose level
screened (phenindamine confers the same protection at 10
mg/kg). The log P values (Table 1) for pairs of isomers are
consistently higher for the 9,9a-ene compared with the
4a,9a-ene as induced co-planarity, through the conjugated
system, between the ene and the 9-aryl substituent,
enhances lipophilicity, which can a€ect drug distribution.
The next group of compounds described, 15±22, di€er
in the position of the double bond which remains fol-
lowing the partial reduction of the precursor dienes (e.g.,
12±14). In previous work, the outcome of this reduction
to either a 9,9a-ene (15±18) or a 4a,9a-ene (19±22) was
dependent upon which proton salt was used to isolate the
reduced product, though not in a consistent way.2,12,13
We have recently established predictable methods for the
selection of one or other of the reduction products.8 The
IC50 values of the N-methyl 9,9a-ene, 15 (28 nM) is close
to that of the 4a,9a-ene (and mepyramine, the test sub-
stance), showing that the two compounds are of similar
anity at this receptor. Previous reports suggested that
the majority of biological activity resides in the latter,
geometric isomer. This discrepancy is even more pro-
nounced in the case of the N-benzyl analogues (17 and 21)
where the former 9,9a-isomer is over 40 times as active as
its 4a,9a-isomer and has an activity 3±4 times that of both
standard test substances. However, as with results for
piperidines 1 and 2 these antagonistic properties did not
Di€ering conformations in the two enes may also con-
tribute to these di€erences allowing one to comply more
closely with the 3-dimensional criteria previously identi-
®ed21 for activity at this receptor, and o€ering a more sui-
tably-disposed 9-aryl substituent to the receptor.
Within the fully reduced series, 23±25, derived from either
of the corresponding dienes or monoenes by a more vig-
orous reduction with platinum, little or no in vivo activity
was seen. The all-cis compound 23 (R1=Me, R2=H,
conventionally so described; H-4a, 9- and 9a- all on same
face of tricyclic nucleus) was inactive providing no pro-
tection against 48/80 with both mice dying at 36 min.

C. Upton et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1277±1279
1279
The H-9 epimer 24 of compound 23 had an ED50 of 40
mg/kg and 25 (all cis, R1=Me, R2=Et) was ine€ective
at these doses.
4. Casy, A. F.; Ganellin, C. R.; Mercer, A. D.; Upton, C. J.
Pharm. Pharmacol. 1992, 44, 791.
5. Ja€ar, M.; Upton, C. J. Pharm. Pharmacol. 1996, 48, 444.
6. Salunga, T. L.; Han, X. Y.; Wong, S. M.; Takeuchi, H.;
Matsunami, K.; Upton, C.; Mercer, A. D. Eur. J. Pharmacol.
1996, 304, 163.
7. Upton, C.; Ja€ar, M. Pharm. Sci. 1996, 2, 411.
8. Upton, C.; Ja€ar, M. J. Pharm. Pharmacol. 1998, 50, 829.
9. Kubela, R.; DoNascimento, J. M. 1977 for Delmer Chemi-
cals Ltd., German Patent: Ger. O€en. 2,600,557, July 1977;
Chem. Abs. 1978, 88P, 6727f.
10. Stenlake, J. B.; Patrick, G. L.; Sneader, W. E. Eur. J. Med.
Chem. 1989, 24, 591.
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P. A.; Anderson, S. A.; Gu, Y. Q.; Petrow, V. J. Med. Chem.
1995, 38, 753.
12. Plati, J. T.; Wenner, W. J. Org. Chem. 1949, 14, 543.
13. Plati, J. T.; Wenner, W. J. Org. Chem. 1955, 20, 1412.
14. Brimblecombe, R. W.; Green, D. M.; Inch, T. D.; Thomp-
son, B. J. J. Pharm. Pharmacol. 1971, 745
In conclusion, it is clear from the IC50 results that H1-
antagonist activity is not restricted solely to the 2,3,4,9-
tetrahydroindeno[2,1-c]pyridine nucleus, (the 4a,9a-
enes), as previously thought. In the case of 15, the
9,9a-ene, it exhibits activity comparable to the two test
substances, phenindamine and mepyramine, and the N-
benzyl 9,9a-ene, 17, is 3±4 times as active as these stan-
dards. Notably its 4a,9a-isomer 21 has less than one
fortieth of the activity of the 9,9a-ene. Furthermore, H1
antagonism seems apparent in the even more con-
formationally-restricted dienes such as 12. Similarly, this
previously unreported activity in the precursor piper-
idines such as 1 and 2 also o€ers new potential avenues
for investigation.
15. Niemegeers, C. J. E.; Awouters, F.; Van Neuten, J. M.; De
Nollin, S.; Janssen, P. J. A. Arch. Int. Pharmacodyn. Ther. 1978,
234, 164.
Acknowledgements
16. Determined using software from Advanced Chemical Co.,
San Francisco; we have recently shown17 that results obtained
from this package compare favourably with those derived
using Clog P and KOWWIN software, the most highly rated
for this purpose.18
The authors wish to thank Mr. K. Schellekens (Janssen
Pharmaceutica, Belgium) for the 48/80 test results.
17. Upton, M.; Upton, C. Mutagenesis 1999, 14, 101.
18. Mannhold, R.; Dross, K. Quant. Struct.-Act. Relat. 1996, 15,
403.
References and Notes
1. Branch, S. K.; Casy, A. F.; Hussain, R. B.; Upton, C. J.
Pharm. Pharmacol. 1988, 40, 83.
19. Casy, A. F.; Beckett, A. H.; Iorio, M. A. Tetrahedron 1967,
23, 1405.
2. Casy, A. F.; Hussain, R. B.; Upton, C. Mag. Reson. Chem.
1992, 30, 621.
3. Casy, A. F.; Drake, A. F.; Ganellin, C. R.; Mercer, A. D.;
Upton, C. Chirality 1992, 4, 356.
20. Hardy, R.A.; Howell, M.G. In Medicinal Chemistry; de
Stevens, G., Ed.; Academic: New York, 1965; Vol. 5, pp 196±206.
21. Borea, P. A.; Bertolasi, V.; Gilli, G. Arzneim.-Forsch. 1986,
36, 895.