L. Provins et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1834–1839
1839
17. Provins, L.; Christophe, B.; Danhaive, P.; Dulieu, J.;
around the 4,6-diaminopyrimidine scaffold allowed us to
identify ucb-101333-3 which has been selected for exten-
sive DMPK and pharmacological evaluation on the ba-
sis of its excellent affinity/activity and selectivity profiles
as well as adequate physicochemical properties. Those
results as well as its characterization in relevant animal
models of COPD will be reported in due course.
´
Durieu, V.; Gillard, M.; Lebon, F.; Lengele, S.; Quere, L.;
van Keulen, B. J. Sci. Pharm. 2005, 73, S180.
´ ´
18. Gershon, H.; Braun, R.; Scala, A.; Rodin, R. J. Med.
Chem. 1964, 7, 808.
19. Biagi, G.; Giorgi, I.; Livi, O.; Scartoni, V.; Lucacchini, A.
Farmaco 1997, 52, 61.
20. Beck, J. P.; Arvanitis, A. G.; Curry, M. A.; Rescinito, J.
T.; Fitzgerald, L. W.; Gilligan, P. J.; Zaczek, R.; Trainor,
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Acknowledgments
21. Chen, C.; Dagnino, R.; De Souza, E. B.; Grigoriadis, D.
E.; Huang, C. Q. J. Med. Chem. 1996, 39, 4358.
22. Chorvat, R. J.; Bakthavatchalam, R.; Beck, J. P.;
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´
The authors thank Geraldine Longfils for compounds’
crystallization, Bernadette Norberg (FUNDP, Namur)
for X-ray resolution, Liliane Ellens for technical support
23. Inhibition of PDE4 enzyme activity was measured in the
supernatant from U937 cells prestimulated with salbuta-
mol and rolipram to upregulate PDE4 expression. Enzyme
activity was measured using [3H]cAMP as a substrate.
24. Affinity for M3 muscarinic receptor was determined by
competition experiments with [3H]N-methylscopolamine
performed in CHO cell membranes expressing recombi-
nant human receptors.
´
in physicochemistry, and Veronique Pinilla and her
team for chiral chromatography.
References and notes
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25. Capacity factors (k0IAM) were established on
IAM.PC.DD Drug-Discovery HPLC column
a
2
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26. Separation of the diastereoisomers has been performed via
chiral chromatography (Daicel Chiralpak AD column).
27. All titrations were performed using a GlpKaTM (Sirius,
Forest Row, UK) and done in aqueous solution or
methanol–water mixture with 0.15 M KCL at 25 ꢂC using
standardized 0.5 M HCL titrant.
28. CCDC 290973 contains the supplementary crystallograph-
ic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
29. CCDC 290974 contains the supplementary crystallograph-
ic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
30. Christophe, B.; Lelubre, F.; Provins, L.; Peck, M.;
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