title: 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.
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Avenue, m/c 870, Chicago, IL 60607-7173, USA.
authors.forename: Sochanchingwung
authors.initials: S
authors.lastname: Rumthao
authors.forename: Oukseub
authors.initials: O
authors.lastname: Lee
authors.forename: Qi
authors.initials: Q
authors.lastname: Sheng
authors.forename: WenTao
authors.initials: W
authors.lastname: Fu
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Mulhearn
authors.forename: David
authors.initials: D
authors.lastname: Crich
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mesecar
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
mesh_terms: 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
chemical_list: D000438:Alcohols; D000588:Amines; D000838:Anions; D001550:Benzamidines; D065427:Factor Xa Inhibitors; D013450:Sulfones; D015951:Factor Xa