Applying the pro-drug approach to afford highly bioavailable antagonists of P2Y sub(14)

Our series of competitive antagonists against the G-protein coupled receptor P2Y sub(14 were found to be highly shifted in the presence of serum (99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwi...

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Published inBioorganic & medicinal chemistry letters Vol. 21; no. 14; pp. 4366 - 4368
Main Authors Robichaud, Joel, Fournier, Jean-Francois, Gagne, Sebastien, Gauthier, Jacques Yves, Hamel, Martine, Han, Yongxin, Henault, Martin, Kargman, Stacia, Levesque, Jean-Francois, Mamane, Yael, Mancini, Joseph, Morin, Nicolas, Mulrooney, Erin, Wu, Jin, Black, WCameron
Format Journal Article
LanguageEnglish
Published 15.07.2011
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Summary:Our series of competitive antagonists against the G-protein coupled receptor P2Y sub(14 were found to be highly shifted in the presence of serum (99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared ( 7a- 7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.)
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ISSN:0960-894X
DOI:10.1016/j.bmcl.2010.12.113