J.-U. Peters et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3405–3408
3407
Table 2
NH2
NHBoc
NO2
a
b
Inhibition of NK1 agonist (GR73632)-induced foot tapping behaviour in Mongolian
gerbils after oral pretreatment of animals with 1 and 10 2 h prior to intracerebro-
ventricular (icv) administration of the agonist15
Cl
N
Cl
N
Cl
N
3
4
5
Compd
ID50 (mg/kg, po)
1.0
Single dose, 10 mg/kg, po
1
I
I
10c
10d
10n
10o
100% inhibition
100% inhibition
N
NHBoc
c
d
e
Boc
2
1.3
1.1
Cl
N
Cl
N
6
7
out of which one compound, 10l, had a greatly improved NK3
receptor affinity and a balanced profile. Interestingly, the N–C–C–
OH conformation of such ‘exocyclic’ derivatives overlaps with the
conformation observed in the X-ray analysis of 1 (Fig. 2), and 10l
may thus be regarded as a conformationally restricted analogue
of 1. Compound 10l was further modified by the introduction of
additional OH groups, which was postulated to further improve
the NK3 receptor affinity (see above). This led to 10n and 10o,
which may be regarded as locked analogues of 10e. Although the
NK3 receptor affinity of 10n and 10o was not improved in
comparison to 10e or 10l, both compounds had high and balanced
NK1/NK3 receptor affinities. A comparison of 10p and 10o demon-
strates that a free hydroxyl group is still needed for high NK3
receptor affinity in these compounds: methylation of the hydroxyl
groups of 10o leads to a ꢀ15-fold reduction of NK3 receptor affin-
ity. Finally, 10q was found to be another bis-hydroxylated ana-
logue of 10l with a well-balanced affinity ratio. Formally, 10q is
a ring-closed analogue of 10e, although binding conformations
and the spacial orientation of the hydroxyl groups may be differ-
ent. Out of these and many similar compounds, 10e,f,l,n,o emerged
as being best in terms of high and balanced affinities for the hNK1
and the hNK3 receptors.
Cl
Cl
Cl
Cl
f
g
NH
N
CF3
O
N
N
CF3
8
9
R
NH
Cl
R
N
CF3
h
R
O
N
N
R
CF3
10
Scheme 1. Preparation of building block 2, and final products 10. Reagents and
conditions: (a) Fe, HCl, H2O, 30 min, 90 °C, 70%; (b) NaHMDS, Boc2O, THF, 2 h, rt,
81%; (c) BuLi, TMEDA, I2, Et2O, 16 h, rt, 50%; (d) NaH, MeI, DMF, 3.5 h, À10 °C,
quant.; (e) TFA, CH2Cl2, 2 h, rt, quant.; (f) 2-chlorophenylboronic acid, Pd(OAc)2,
PPh3, 2 N Na2CO3, DME, 80 °C, 2 h, 89%; (g) KHMDS, add 2-(3,5-bis-trifluoromethyl-
phenyl)-2-methyl-propionyl chloride,13 THF, rt, 30 min, 80%; (h) typical conditions:
R2NH/DMSO = 1:1, 130 °C, 1–3 d.14
In a preliminary evaluation of in vivo properties, 10n and 10o
dose-dependently inhibited NK1 agonist (GR73632)-induced foot
tapping behaviour in gerbils16 with an ID50 of 1.3 and 1.1 mg/kg,
respectively, indicating NK1 antagonistic activity after oral admin-
istration (Table 2). Similarly, 10c and 10d led to a complete block-
ade of NK1 agonist induced foot tapping after 10 mg/kg (single dose
po). These results demonstrate that the molecular properties of
these compounds are suitable to reach the intended target in the
CNS after oral administration, and to elicit the expected pharmaco-
dynamic response with a reasonable dose.
In conclusion, the serendipitously discovered dual NK1/NK3
receptor ligand 1 was optimised into a lead series represented by
10e,f,l,o with high and balanced affinities for the NK1 and NK3
receptors. Compounds 10n and 10o elicited a dose-dependent
pharmacodynamic response in vivo. A novel synthetic access to
compounds 10 via a versatile building block 2 was developed,
and a preliminary SAR for NK3 receptor affinity was elucidated.
These results provided the basis for a lead optimisation program
towards a novel antipsychotic treatment.
amounts. Although the use of building block 2 would allow for a
derivatisation of three vectors (Fig. 1), we decided initially to focus
on the amine substituent, which was likely responsible for the NK3
receptor affinity of 1. To this end, we converted 2 via 8 into the ad-
vanced building block 9 by a Suzuki coupling with a sterically hin-
dered ortho-substituted arylboronic acid, followed by an acylation.
Both steps proceeded in good overall yields. The 2-chloropyridine
motif in 9 was found to be quite unreactive towards amines, and
high temperatures, a large excess of amines, and long reaction
times were necessary to obtain the desired target compounds,
10.14 Nevertheless, this final step (Scheme 1, h) was well amenable
to parallel chemistry, and numerous end-products 10 were
obtained from 9 and a variety of amines.15
Affinities of compounds 10a–q for the hNK1 and the hNK3
receptors were determined using radioligand binding assays;14
the results for selected compounds are presented in Table 1.
Almost all compounds had low- to sub-nanomolar affinities for
the NK1 receptor. A comparison of 1 with 10a demonstrated that
the methylation of the hydroxyl function leads to a ꢀeightfold
reduction in NK3 receptor affinity, which supported our working
hypothesis, that a free hydroxyl group is needed for high NK3 affin-
ity. The introduction of an N-methyl substituent improved the NK3
receptor affinity (10b compared to 1). Homologues (10c and 10d)
had no further increased NK3 affinities, but the introduction of a
second hydroxyl function into this side chain led to potent and bal-
anced NK1/NK3 receptor ligands (10e and 10f). The modulation of
the receptor binding profile by conformational locking was further
explored with cyclic amine substituents. The ‘endocyclic’ incorpo-
ration of the ethylene linker into a piperidine or a pyrrolidine ring
led to compounds with retained affinities for both receptors (10g–i
compared to 1). ‘Exocyclic’ linker incorporation resulted in 10j–m,
Acknowledgements
The excellent technical assistance of Guido Achermann, Nadia
Anastasi, Cosimo Dolente, Philipp Ernst, Marie Haman, Catherine
Hamm, Stéphane Henriot, Julien Heusser, Stéphane Kritter, Cather-
ine Muller, Gabrielle Py, Alain Rudler, Stefanie Saenger, Silja
Weber, Severine Weil-Bandinelli and Roger Wyler is gratefully
acknowledged.
References and notes
1. van Os, J.; Kapur, S. Lancet 2009, 374, 635.
2. Sneader, W. Drug News Perspect. 2002, 15, 466.
Peters, Jens-Uwe
