The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.
Publication
, Journal Article
Gauthier, JY; Belley, M; Deschênes, D; Fournier, J-F; Gagné, S; Gareau, Y; Hamel, M; Hénault, M; Hyjazie, H; Kargman, S; Lavallée, G; Li, L ...
Published in: Bioorganic & medicinal chemistry letters
May 2011
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.
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Published In
Bioorganic & medicinal chemistry letters
DOI
EISSN
1464-3405
ISSN
0960-894X
Publication Date
May 2011
Volume
21
Issue
10
Start / End Page
2836 / 2839
Related Subject Headings
- Uridine Diphosphate
- Structure-Activity Relationship
- Receptors, Purinergic P2Y
- Receptors, Purinergic P2
- Purinergic P2 Receptor Antagonists
- Protein Binding
- Pan troglodytes
- Naphthalenes
- Molecular Structure
- Mice
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Gauthier, J. Y., Belley, M., Deschênes, D., Fournier, J.-F., Gagné, S., Gareau, Y., … Black, W. C. (2011). The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14. Bioorganic & Medicinal Chemistry Letters, 21(10), 2836–2839. https://doi.org/10.1016/j.bmcl.2011.03.081
Gauthier, Jacques Yves, Michel Belley, Denis Deschênes, Jean-François Fournier, Sébastien Gagné, Yves Gareau, Martine Hamel, et al. “The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.” Bioorganic & Medicinal Chemistry Letters 21, no. 10 (May 2011): 2836–39. https://doi.org/10.1016/j.bmcl.2011.03.081.
Gauthier JY, Belley M, Deschênes D, Fournier J-F, Gagné S, Gareau Y, et al. The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14. Bioorganic & medicinal chemistry letters. 2011 May;21(10):2836–9.
Gauthier, Jacques Yves, et al. “The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.” Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 10, May 2011, pp. 2836–39. Epmc, doi:10.1016/j.bmcl.2011.03.081.
Gauthier JY, Belley M, Deschênes D, Fournier J-F, Gagné S, Gareau Y, Hamel M, Hénault M, Hyjazie H, Kargman S, Lavallée G, Levesque J-F, Li L, Mamane Y, Mancini J, Morin N, Mulrooney E, Robichaud J, Thérien M, Tranmer G, Wang Z, Wu J, Black WC. The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14. Bioorganic & medicinal chemistry letters. 2011 May;21(10):2836–2839.
Published In
Bioorganic & medicinal chemistry letters
DOI
EISSN
1464-3405
ISSN
0960-894X
Publication Date
May 2011
Volume
21
Issue
10
Start / End Page
2836 / 2839
Related Subject Headings
- Uridine Diphosphate
- Structure-Activity Relationship
- Receptors, Purinergic P2Y
- Receptors, Purinergic P2
- Purinergic P2 Receptor Antagonists
- Protein Binding
- Pan troglodytes
- Naphthalenes
- Molecular Structure
- Mice