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

Abstract：

: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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Robichaud J,Fournier JF,Gagné S,Gauthier JY,Hamel M,Han Y,Hénault M,Kargman S,Levesque JF,Mamane Y,Mancini J,Morin N,Mulrooney E,Wu J,Black WC

doi

10.1016/j.bmcl.2010.12.113

subject

Has Abstract

pub_date

2011-07-15 00:00:00

pages

4366-8

issue

14

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(10)01877-9

journal_volume

21

pub_type

杂志文章

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