A novel factor Xa inhibitor: structure-activity relationships and selectivity between factor Xa and thrombin.
A series of 3-amidinoaryl-2-[4-[ [(3S)-3-pyrrolidinyl]oxy]phenyl] propanoic acids have been investigated for development of a novel factor Xa inhibitor, possessing a potent inhibitory activity for factor Xa and a selectivity for factor Xa compared to thrombin. In order to study the structure-activity relationships and the selectivity, models of factors Xa complexes formed with the inhibitors were constructed on the basis of X-ray crystallographic data of a trypsin-inhibitor complex. The models showed that the binding mode of the inhibitors to the S1 pocket of the enzyme accounted for the structure-activity relationships and that the difference between Gln192 of factor Xa and Glu192 of thrombin had a key role in the selectivity.
Katakura
S
S
Exploratory Research Laboratories 2, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Nagahara
T
T
Hara
T
T
Iwamoto
M
M
D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D005973:Glutamine; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011487:Protein Conformation; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014357:Trypsin / Q000737:chemistry
D000578:Amidines; D065427:Factor Xa Inhibitors; D011422:Propionates; D011480:Protease Inhibitors; D011759:Pyrrolidines; D005973:Glutamine; D014357:Trypsin; D013917:Thrombin; D015951:Factor Xa