Design, synthesis, and evaluation of oxyanion-hole selective inhibitor substituents for the S1 subsite of factor Xa.
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.
Rumthao
Sochanchingwung
S
Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Avenue, m/c 870, Chicago, IL 60607-7173, USA.
Lee
Oukseub
O
Sheng
Qi
Q
Fu
WenTao
W
Mulhearn
Debbie C
DC
Crich
David
D
Mesecar
Andrew D
AD
Johnson
Michael E
ME
D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry; D000838:Anions / Q000737:chemistry; D001550:Benzamidines / Q000138:chemical synthesis / Q000737:chemistry; D020134:Catalytic Domain; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry
D000438:Alcohols; D000588:Amines; D000838:Anions; D001550:Benzamidines; D065427:Factor Xa Inhibitors; D013450:Sulfones; D015951:Factor Xa