S. Fonquerna et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1165–1167
1167
O
O
cross blood–brain barrier compared to compound 1
and therefore less sedative properties should be ex-
pected. Finally, the potential to cause adverse cardiac
adverse effects was also assessed for compounds 19, 20
and 21. The effect in the QT prolongation interval was
measured in anesthetised guinea-pigs at a prefixed dose
of 10 mg/kg and compounds 19, 20 and 21 did not pro-
duce any significant increase.
*
OH
OH
*
R3
O
R4
A
B
C
R3 = H
3 = OMe
R3 = Cl
D
E
R3 = H
3 = OMe
R
R
Figure 1. Substituents for R1 in Table 1.
Regarding solubility in water, compounds from the pyr-
rolopyridinepiperidine series showed typically at least a
2-fold increase when comparing to structural equivalent
ones from the previous series. The range of solubility
moved from 1224 lg/mL (compound 2) to 115 lg/mL
(compound 20) whereas in the previous series the values
of solubility obtained ranged between 100 lg/mL (com-
pound 1) and 22 lg/mL.
low sedative potential. From the extensive optimisation
work carried out within this series, other promising
candidates with long duration of action in vivo and
better pharmacokinetic profile were identified.4
In order to evaluate the impact of the substitution of the
indole group by a pyrrolopyridine moiety a selected set
of compounds were synthesised and their pharmacolog-
ical profiles are reported in Table 1.
In conclusion, we have identified a new series of potent
and selective H1 antagonists. We also have discovered
that the nature of the acid chain bond to piperidine is
a key feature for maintaining both the duration of ac-
tion in vivo and lack of sedative properties. Further
work is underway and will be reported in due course.
Compound 2, with identical pattern of substitution as
compound 1, showed similar in vitro and in vivo H1
activities with enhanced selectivity versus 5HT2.
Encouragingly, compound 2 had a 4-fold reduced seda-
tive potential measured in the H1 ex vivo assay. This
interesting result prompted us to synthesise other deriva-
tives with selected substitution in R2 previously known
to provide long duration of action in the indolylpiper-
idine series. Maintaining the ethoxyethyl chain in R2,
we then proceeded to explore several substituents on
the piperidine. As a general trend, we obtained com-
pounds (6, 14 and 18) with high in vivo potencies similar
to compound 1 in spite of the fact that 14 and 18 showed
lower in vitro H1 activity. Moreover, compounds 6 and
14 showed an interesting 2-fold reduction of sedative
potential compared to 1.
References and notes
1. Bousquet, J.; Van Cauwenberge, P.; Khaltaev, N. J. Allergy
Clin. Immunol. 2001, 108, S147–S334.
2. Kay, G. G. J. Allergy Clin. Immunol. 2000, 105, S622–S627.
3. Dubuske, L. M. Clin. Ther. 1999, 21, 281–295.
4. Fonquerna, S.; Miralpeix, M. J. Med. Chem. 2004, 47,
6326–6337.
5. Chang, R. S.; Tran, V. T. J. Neurochem. 1979, 32, 1653–
1663.
6. Pazos, A.; Hoyer, D.; Palacios, J. M. Eur. J. Pharmacol.
1985, 106, 531–538.
7. Greengrass, P.; Bremner, R. Eur. J. Pharmacol. 1979, 55,
323–326.
8. Leysen, J. E.; Gommeren, W.; Janssen, P. F. M.; Janssen,
P. A. J. Drug Dev. Res. 1991, 22, 165–178.
9. Llenas, J.; Gras, J.; Palacios, J. M.; Roberts, D. J. Allergy
Clin. Immunol. 1999, 103, S256.
The most promising benzoic acid chain was E (Fig. 1) as
all the compounds containing this group showed high in
vivo potencies after 4 h and in particular compounds 19,
20 and 21 showed long duration of action keeping activ-
ity after 8 h. Furthermore, compound 20 and particu-
larly 19 and 21 proved to have a reduced capacity to