G. Capozzi et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2263–2266
2265
ligands for the human tachykinin NK-2receptor. Fur-
ther work, aimed to improve affinity through the inser-
tion on the scaffold of more complex aromatic or
heteroaromatic moieties (such as indole in 1), will be
reported in due time.
References and Notes
1. Maggi, C. A.; Patacchini, R.; Rovero, P.; Giachetti, A.
J. Auton. Pharmacol. 1993, 13, 2 3.
2. Emonds-Alt, X.; Proietto, V.; Van Broeck, D.; Vilain, P.;
Advenier, C.; Neliat, G.; Le Fur, G.; Breliere, J. C. Bioorg.
Med. Chem. Lett. 1993, 3, 925.
3. Catalioto, R.-M.; Criscuoli, M.; Cucchi, P.; Giachetti, A.;
Giannotti, D.; Giuliani, S.; Lecci, A.; Lippi, A.; Patacchini,
R.; Quartara, L.; Renzetti, A. R.; Tramontana, M.; Arca-
mone, F.; Maggi, C. A. Br. J. Pharmacol. 1998, 124, 81.
4. Lombardi, A.; D’Auria, G.; Saviano, M.; Maglio, O.;
Nastri, F.; Quartara, L.; Pedone, C.; Pavone, V. Biopolymers
1997, 40, 505.
5. Lombardi, A.; D’Auria, G.; Maglio, O.; Nastri, F.; Quar-
tara, L.; Pedone, C.; Pavone, V. J. Am. Chem. Soc. 1998, 120,
5879.
6. Renzetti, A. R.; Catalioto, R.-M.; Criscuoli, M.; Cucchi,
P.; Ferrer, C.; Giolitti, A.; Guelfi, M.; Rotondaro, L.; Warner,
F. J.; Maggi, C. A. J. Pharmacol. Exp. Ther. 1999, 290, 487.
7. Giolitti, A.; Cucchi, P.; Renzetti, A. R.; Rotondaro, L.;
Zappitelli, S.; Maggi, C. A. Neuropharmacology 2000, 39,
1422.
8. Giannotti, D.; Perrotta, E.; Di Bugno, C.; Nannicini, R.;
Harmat, N. J. S.; Giolitti, A.; Patacchini, R.; Renzetti, A. R.;
Rotondaro, L.; Giuliani, S.; Altamura, M.; Maggi, C. A.
J. Med. Chem. 2000, 43, 4041.
Scheme 1.
9. Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino,
J.; Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B.,
III; Strader, C. D.; Cascieri, M. A.; Candelore, M. R.;
Donaldson, C.; Vale, W.; Maechler, L. J. Am. Chem. Soc.
1992, 114, 9217.
10. Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy,
E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.;
Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith,
A. B., III; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson,
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J. Am. Chem. Soc. 1993, 115, 12550.
group at C-3 unessential. On the other hand, the pre-
sence of one or two aromatic groups on the oxathiinic
moiety does not seem to have any effect on the affinity
as shown by the comparison between 18 and 27. Given
the strong difference in bulkiness, it likely appears that
these residues are accommodated in a steric-free region
of the receptor, probably towards the extracellular side.
On the other hand 20, which bears only two aromatic
moieties, still shows a submicromolar affinity to the
NK-2receptor. This is probably index of a different
binding mode for this compound.
11. Sofia, M. J. Med. Chem. Res. 1998, 8, 362.
12. Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt,
W.; Kunz, H. Angew. Chem., Int. Ed. 1998, 37, 2503.
13. Capozzi, G.; Dios, A.; Franck, R. W.; Geer, A.; Marza-
badi, C.; Menichetti, S.; Nativi, C.; Tamarez, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 777.
An increase in activity was repeatedly shown going from
the sulfides to the corresponding sulfoxides (see 15 vs
16, 17 vs 18, 26 vs 27). This seems to be an interesting
point, not completely unexpected considering that one
of the most studied nonpeptide antagonists, the Glaxo
sulfoxide compound GR 15969720 was reported to have
increased NK-2affinity (one order of magnitude)
respect to the parent sulfide. However, further oxidation
to the sulfone 28 only led to a decrease in activity.
14. Capozzi, G.; Franck, R. W.; Mattioli, M.; Menichetti, S.;
Nativi, C.; Valle, G. J. Org. Chem. 1995, 60, 6416.
15. The tribenzylglucal 2 and the dibenzylglucals 3 and 5 were
prepared treating a suspension of NaH in DMF with d-(+)glu-
cal. After 30 min stirring at rt, the mixture was cooled to 0 ꢀC
and an excess of benzyl bromide was added. The reaction, com-
plete after 24 h stirring at rt, was quenched with H2O and the
mixture extracted with CH2Cl2. Flash column chromatography
afforded 2 (25%), 3 (20%), 5 (16%) and small amounts of
monobenzylated glucals, easily separable from tri- and di-benzy-
lated derivatives. The monobenzylglucal 6 and the dibenzylglucal
4 were obtained from 3,6-O-di tertbutyldimethylsilylglucal and
6-O-tertbutyldimethylsilylglucal16 as starting material respec-
tively, following the above reported procedure.
Compounds of Table 1 showed antagonist activity in
functional experiments on isolated endothelium-
deprived rabbit pulmonary artery preparations when
evaluated against a contractile concentration–response
curve to NKA (pKB=6.0 for 18).21
In conclusion, we have shown that a glucose-oxathiinic
scaffold, suitably substituted with simple aromatic moi-
eties, can be used to obtain nonpeptide micromolar
16. For the silylation of glycals, see: Capozzi, G.; Falciani, C.;
Menichetti, S.; Nativi, C.; Raffaelli, B. Chem. Eur. J. 1999, 6,
1748.