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Design, synthesis, and evaluation of oxyanion-hole selective inhibitor substituents for the S1 subsite of factor Xa.

Abstract：

:We have designed, synthesized, and evaluated the factor Xa inhibitory activities of p-amidinophenyl-sulfones, amines, and alcohols intended to take advantage of the polarity and hydrogen-bonding potential of the oxyanion hole region of the S1 specificity pocket. We demonstrate that placement of an anionic group within the oxyanion hole region of the catalytic site substantially enhances activity, with small flexible groups favored over bulkier ones. Ab initio pKa calculations suggest that the hydroxyl substituent frequently used for benzamidine moieties may be ionized to form an anionic group, consistent with the general trend. One nonamidine based substituent also shows promising activity.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Rumthao S,Lee O,Sheng Q,Fu W,Mulhearn DC,Crich D,Mesecar AD,Johnson ME

doi

10.1016/j.bmcl.2004.07.054

subject

Has Abstract

pub_date

2004-10-18 00:00:00

pages

5165-70

issue

20

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(04)00955-2

journal_volume

14

pub_type

杂志文章

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