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Bioorg Med Chem Lett. 2011 Jul 15;21(14):4366-8. doi: 10.1016/j.bmcl.2010.12.113. Epub 2010 Dec 28.

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

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Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy., Kirkland, Quebec, Canada H9H 3L1.


Our series of competitive antagonists against the G-protein coupled receptor P2Y(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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