T. Ginsburg-Shmuel et al. / Bioorg. Med. Chem. 20 (2012) 5483–5495
5495
P–B bond to acidic hydrolysis, as compared to that of the P–O
bond.42 Even so, a half-life of 16.9 h is quite satisfactory for a drug
14. Besada, P.; Shin, D. H.; Costanzi, S.; Ko, H.; Mathe, C.; Gagneron, J.; Gosselin, G.;
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candidate. (B) The BH
tance to degradation by NPP1,3. The introduction of the borano-
phosphate moiety at P plays an important role in protecting
UDP analogues against NPP1,3 hydrolysis. The enzymatic degrada-
tion by NPP occurs between P and P . Yet, since BH group in ana-
logue 18A is larger than O in the parent compound, it possibly
prevents an attack by an essential water molecule on P and makes
3 a
substitution at P position increases resis-
1
7. Ko, H.; Carter, R. L.; Cosyn, L.; Petrelli, R.; de Castro, S.; Besada, P.; Zhou, Y.;
Cappellacci, L.; Franchetti, P.; Grifantini, M.; Van Calenbergh, S.; Harden, T. K.;
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a
a
b
3
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80, 16909.
these analogues poor NPP substrates. Furthermore, analogue 8,
bearing only a modification at the uracil ring, was hydrolyzed more
20. Kim, H. S.; Ravi, R. G.; Marquez, V. E.; Maddileti, S.; Wihlborg, A.-K.; Erlinge, D.;
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slowly by NPP3, but not by NPP1 as compared to 4. (C) The BH
substitution at P position and OMe at the C5 position of uracil
3
21. Mamedova, L. K.; Joshi, B. V.; Gao, Z.-G.; von Kugelgen, I.; Jacobson, K. A.
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nucleotides increase resistance to degradation in human blood ser-
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and 31A renders the nucleotides even more stable to enzymatic
degradation than 4.
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2
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1
more potent than the endogenous agonist, 4, at the P2Y
we identified 5-OMe-UDP( -B) R isomer, 18A, as the most potent
and selective agonist at the P2Y -R currently known, being 19-fold
more potent than 4. The combination of two substitutions—a meth-
oxy at the UDP C5 position and a BH group at the P position,
6
-R. Here,
31. Eliahu, S. E.; Camden, J.; Lecka, J.; Weisman, G. A.; Sevigny, J.; Gelinas, S.;
a
p
Fischer, B. Eur. J. Med. Chem. 2009, 44, 1525.
6
32. Joseph, S. M.; Pifer, M. A.; Przybylski, R. J.; Dubyak, G. R. Br. J. Pharmacol. 2004,
42, 1002.
1
3
3. Boyle, N. A.; Rajwanshi, V. K.; Prhavc, M.; Wang, G.; Fagan, P.; Chen, F.; Ewing,
G. J.; Brooks, J. L.; Hurd, T.; Leeds, J. M.; Bruice, T. W.; Cook, P. D. J. Med. Chem.
2005, 48, 2695.
3
a
which presented another chiral center—greatly increased the ago-
nist activity of the previously discovered agonist 8. Compound
8A exhibits a half-life of 16.9 h under conditions simulating gastric
3
4. Eliahu, S.; Martin-Gil, A.; Perez de Lara, M. J.; Pintor, J.; Camden, J.; Weisman, G.
A.; Lecka, J.; Sévigny, J.; Fischer, B. J. Med. Chem. 2010, 53, 3305.
5. Holy, A. Curr. Pharm. Des. 2003, 9, 2567.
1
3
juice acidity, and improved resistance to enzymatic degradation by
NPP1 and NPP3 as compared to UDP, 4, (15% vs 50% and 28% vs 45%
degradation, respectively). Furthermore, the borane group induced
a sevenfold increased stability (t1/2 17 h) in human blood serum as
36. De Clercq, E.; Holy, A. Nat. Rev. Drug Discov. 2005, 4, 928.
37. Zhou, Z.; Wang, X.; Li, M.; Sohma, Y.; Zou, X.; Hwang, T.-C. J. Physiol. 2005, 569,
4
47.
8. Major, D. T.; Nahum, V.; Wang, Y.; Reiser, G.; Fischer, B. J. Med. Chem. 2004, 47,
405.
3
4
compared to the endogenous P2Y
eficial pharmacological properties of 18A prompted us to explore
its therapeutic potential, which will be reported in due course.
6
-R agonist, 4 (t1/2 2.4 h). The ben-
39. Shaver, S. R.; Rideout, J. L.; Pendergast, W.; Douglass, J. G.; Brown, E. G.; Boyer, J.
L.; Patel, R. I.; Redick, C. C.; Jones, A. C.; Picher, M.; Yerxa, B. R. Purinergic Signal.
2005, 1, 183.
4
4
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Jones, A. C.; Cowlen, M.; Dougherty, R.; Boyer, J.; Abraham, W. M.; Boucher, R.
Supplementary data
11.12.2011.
42. Nahum, V.; Fischer, B. Eur. J. Inorg. Chem. 2004, 4124.
4
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