Synthesis, modelling and NK1 antagonist evaluation of a non-rigid cyclopropane-containing analogue of CP-99,994

Article abstract of DOI:10.1016/S0960-894X(01)00020-8

A non-rigid cyclopropane-containing diamine analogue of CP-99,994 was synthesised and was found to have only moderate NK₁ receptor binding affinity. Molecular dynamics calculations of the conformational space of the former compound gave good co

Full text of DOI:10.1016/S0960-894X(01)00020-8

Bioorganic & Medicinal Chemistry Letters 11 (2001) 659±661
Synthesis, Modelling and NK1 Antagonist Evaluation of a
Non-Rigid Cyclopropane-Containing Analogue of CP-99,994
David J. Aitken,a,b,* Sandrine Ongeri,a Danielle Vallee-Goyet,b Jean-Claude Gramainb
and Henri-Philippe Hussona
a
  Á   Â
Laboratoire de Chimie Therapeutique associe au CNRS et a l'Universite Rene Descartes (UMR 8638), Faculte des Sciences
Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75270 Paris cedex 06, France
Â
Á
24 avenue des Landais, 63177 Aubiere cedex, France
b
Â
Laboratoire SEESIB-CNRS (UMR 6504), Departement de Chimie, Universite Blaise Pascal - Clermont-Ferrand II,
Received 23 September 2000; revised 22 December 2000; accepted 2 January 2001
AbstractÐA non-rigid cyclopropane-containing diamine analogue of CP-99,994 was synthesised and was found to have only
moderate NK1 receptor binding anity. Molecular dynamics calculations of the conformational space of the former compound
gave good correlation between observed activity and a recently published pharmacophore model, lending predictive value to the
latter. # 2001 Elsevier Science Ltd. All rights reserved.
The discoveries of CP-96,3451 then CP-99,9942 as the
®rst selective non-peptide NK1 antagonists stimulated
intensive studies of structural analogues throughout the
1990s, in which various aromatic substituents, hetero-
atom replacements and modi®ed molecular frameworks
have been investigated. This research has led to new
potent antagonists, suchas L-733,060, 3 while `minimum
pharmacophore' studies have been carried out to iden-
tify the importance of appropriately placed heteroatoms
and substituted aromatic systems, as in structures 1.4À6
Modelling studies have kept pace with the evolution of
experimental results, culminating in the recent publica-
tion by Marshall's group of a model for the bioactive
conformation of compounds structurally related to CP-
99,345, based on a thorough study of 17 known NK1
antagonists.7 This work identi®ed a precise arrangement
of the aromatic rings as determinant for antagonist
activity.
piperidine (or other) heterocycle, it di€ers from freely
rotating analogues studied hitherto in that both amine
functions are retained in the target structure, while the
cyclopropane moiety might be expected to impose more
conformational restriction8 than in structures such as 1.
This study also presented a timely opportunity to test
Marshall's pharmacophore model with an `unknown'
structural analogue of CP-99,994.
As a contribution to structure±activity studies, we deci-
ded to investigate the cyclopropane compound 2, con-
ceived as a structural analogue of CP-99,994 by rupture
of the piperidine C5±C6 bond and creation of a C5±C3
bond. Although 2 lacks the rigidity imposed by a
Compound 2 was prepared in racemic form using a
strategy designed for 1,2-diamine synthesis using a sim-
ple a-aminonitrile as the starting material,9 as shown in
Scheme 1. Double alkylation of 3 using ethylene sulfate
gave cyclopropane 4 which was transformed into 5 in
three steps. This key intermediate had appropriately-
substituted carbon atoms of the diamine fragment and
*Corresponding author at second address. Tel.: +33-4-73-40-71-84;
fax: +33-4-73-40-77-17; e-mail: aitken@chisg1.univ-bpclermont.fr
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00020-8

660
D. J. Aitken et al. / Bioorg. Med. Chem. Lett. 11 (2001) 659±661
mutually-protected amine functions. The methyl group
was generated by carbamate reduction and the amine
reprotected, giving 6. Liberation of the other amine
function followed by reductive amination using o-anis-
aldehyde led to the penultimate derivative 7, which
furnished 2 upon acidic deprotection (21% overall
yield).10 It was necessary to construct the amine func-
tions in this order, because the alternative intermediate
8 gave only the intractable imidazolidinone 9 under
carbamate reduction conditions.
Pharmacological evaluation of (Æ)-2 was carried out
using standard procedures;11 it had moderate NK1
receptor binding anity, with Ki=150Æ15 nM (com-
pared with Ki=3.1Æ0.9 nM for CP-99,345 in a control
experiment). This shows a similar trend to that observed
for a range of amine-ether derivatives of type 1, for
which the binding anities are reduced by between one
and two orders of magnitude when compared with their
rigid heterocyclic precursors.
A molecular dynamics conformational analysis was
carried out on compound 2 (as its S-enantiomer), and
also on CP-99,994 for comparison purposes.12 For CP-
99,994, two accessible conformer families were found,
corresponding to the two chair forms of the piperidine
ring (of which one was clearly preferred). The lowest
energy conformer had a stacked arrangement of its
two aromatic rings, but a perpendicular (`L-shaped')
conformer (Fig. 1, left) was readily accessible
(ÁE=2.57 kcal molÀ1), corresponding precisely to the
bioactive conformer suggested by Marshall's studies.7
Analogous calculations on 2 showed that three con-
former families were more or less equally attainable,
corresponding (approximately) to staggered conforma-
tions of the N±C±C±N torsion angle. In one of the
families the minimum-energy conformer was found,
again having a stacked aromatic system, and a low-
energy L-shaped conformer (Fig. 1, right) was access-
ible (ÁE=3.06 kcal molÀ1). Superposition of the two
L-shaped conformers (Fig. 1, centre) was achieved with
very good correlation (rmsd=0.215 for six points) and
excellent matching of the pharmacophore aromatic
rings.
Scheme 1. Reagents: (i) LDA±HMPA, THF, À70 ꢀC; (ii) PhLi, THF,
À70 ꢀC to 0 ꢀC; (iii) NaBH4, MeOH; (iv) ClCOOMe, NaOH, CHCl3;
(v) LiAlH4, THF; (vi) H2, Pd(OH)2-C, MeOH; (vii) o-anisaldehyde,
NaBH3CN, HOAc, MeOH; (viii) HBr±HOAc. All reactions at rt
except where speci®ed.
These modelling studies suggest that the presence of the
cyclopropane ring does not severely restrict the acces-
sible conformational space of compound 2. Never-
theless, one low-energy conformer corresponds closely
Scheme 2. Reagents: (i) H2, Pd(OH)2-C, MeOH; (ii) 3,5-bis(tri-
¯uoromethyl)benzaldehyde, NaBH3CN, HOAc, MeOH; (iii) HBr±
HOAc.
Figure 1. L-shaped conformer of CP-99,994 (left). Superposition of the two L-shaped conformers (centre). L-shaped conformer of (S)-2 (right).

D. J. Aitken et al. / Bioorg. Med. Chem. Lett. 11 (2001) 659±661
661
to the putative bioactive conformation of NK1 receptor
antagonists. From these calculations, it would appear
reasonable to predict that structure 2 could behave as
an antagonist, but perhaps not with great potency. This
is indeed borne out by the pharmacology results.
3. Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G.
Bioorg. Med. Chem. Lett. 1994, 4, 2545.
4. Williams, B. J.; Teall, M.; McKenna, J.; Harrison, T.;
Swain, C. J.; Cascieri, M. A.; Sadowski, S.; Strader, C.; Baker,
R. Bioorg. Med. Chem. Lett. 1994, 4, 1903.
5. Swain, C. J.; Cascieri, M. A.; Owens, A. P.; Saari, W.;
Sadowski, S.; Strader, C.; Teall, M.; VanNiel, M. B.; Wil-
liams, B. J. Bioorg. Med. Chem. Lett. 1994, 4, 2161.
6. Owens, A. P.; Williams, B. J.; Harrison, T.; Swain, C. J.;
Baker, R.; Sadowski, S.; Cascieri, M. A. Bioorg. Med. Chem.
Lett. 1995, 5, 2761.
7. Takeuchi, Y.; Shands, E. F. B.; Beusen, D. D.; Marshall,
G. R. J. Med. Chem. 1998, 41, 3609.
8. For leading references on the conformational restrictions
imposed by the presence of a cyclopropane ring, see: Burgess,
K.; Ho, K.-K.; Pettitt, B. M. J. Am. Chem. Soc. 1995, 117, 54.
9. Aitken, D. J. Pharm. Sci. 1997, 3, 319.
Similarly, reduced binding anity was also observed for
another non-rigid cyclopropane-containing analogue
11, this time a hybrid between the CP-99,994 diamine
structure and the ether-amine L-733,060. The previous
synthetic scheme was adapted easily for the preparation
of this compound from intermediate 6, via carbamate 10
(Scheme 2). Pharmacological evaluation11 of (Æ)-11
showed relatively poor receptor binding anity, with
Ki=620Æ30 nM.
10. Data for compound 2: NMR (CDCl3): dH 0.44 (1H, m),
0.53±0.72 (3H, br m), 2.02 (1H, br s), 2.30 (3H, s), 3.67 (1H, s),
3.73 (1H, d, J=12.8), 3.81 (3H, s), 3.99 (1H, d, J=12.8), 5.20
(1H, br s), 6.83 (1H, d, J=7.6), 6.89 (1H, t, J=7.6), 7.18±7.37
(7H, m); dC 11.1 (t), 11.7 (t), 35.3 (q), 43.8 (s), 46.4 (t), 55.3 (q),
68.3 (d), 110.3, 120.7, 127.2, 127.7, 128.2, 129.6 (eachd),
129.4, 141.2, 157.6 (eachs); IR (cm À1): 3533, 3415, 3400 br;
MS(IC): m/z 297 [MH]+; Analytical sample as dihydro-
chloride; mp 147 ꢀC (CHCl3±iPr2O). Anal. calcd for
C19H24N2O 2HCl H2O: C, 58.91; H, 7.29; N, 7.23. Found: C,
59.14; H, 7.09; N, 6.99.
11. Inhibition of [3H][Pro9]-SP was measured using hNK1
receptors expressed in CHO cells, as previously described:
Sagan, S.; Chassaing, G.; Pradier, L.; Lavielle, S. J. Pharma-
col. Exp. Ther. 1996, 276, 1039.
12. Molecular modelling studies were performed on a Silicon
Graphics SGI Power Indigo2 R8000 workstation, using
SYBYL 6.5 software package (Tripos Associates Inc., St
Louis, USA). Structures of CP-99,994 and (S)-2 were built
within SYBYL, the potential types and binding parameters of
the cyclopropane carbons of the latter being de®ned using the
semi-empirical GEOMOS method (Rinaldi, D.; Hoggan, P. E.;
Cartier, A. GEOMOS, QCPE 584). The energy of the mole-
cules was calculated in vacuo withthe Tripos force ®eld Max-
imin2, and minimised directly to ensure the system was in a
low energy state. An elevated temperature of 800 K was
applied for 1000 fs then was reduced to 0 K for 2500 fs. This
process was repeated for 100 cycles so that multiple con-
formations could be generated. Conformers devoid of kinetic
energy were retained, and results were interpreted graphically
for eachmolecule.
In conclusion, this work shows that the above-noted
non-rigid diamine analogues of the CP-99,994-derived
NK1 antagonist family behave similarly to non-rigid
amine-ether derivatives in that they possess diminished
binding anity compared with their heterocyclic pre-
cursors, and demonstrates that Marshall's recent phar-
macophore model may have useful predictive value.
.
.
Acknowledgements
The authors are grateful to A. S. Phimmanao and L.
Chhiv for technical assistance and to Dr. S. Sagan
(CNRS-UMR 7613, Universite Paris VI) for pharma-
cology studies. S.O. thanks the Rectorat des Universites
de Paris for a grant. This work was supported by the
CNRS through AIP funding (to D.J.A.).
References and Notes
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chiya, M. J. Med. Chem. 1992, 35, 2591.
2. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo,
K. P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911.