Rational design, synthesis, and structure-activity relationships of novel factor Xa inhibitors: (2-substituted-4-amidinophenyl)pyruvic and -propionic acids.
An inhibitor of factor Xa (fXa), the m-substituted benzamidine AXC1578 (1a), was structurally modified with the aim of increasing its potency. In particular, pyruvic acid and propionic acid substituents were incorporated into the P1 benzamidine moiety to introduce a favorable interaction with the oxy-anion hole in the catalytic triad region of fXa. This strategy was based on computational docking studies using the extracted active site of fXa. The validity of the computational model was supported by the acquisition of X-ray crystal structures of the 1a-trypsin and 3b-trypsin complexes (the homology around the active sites of fXa and trypsin is high). The above modifications significantly increased the inhibitory activity toward fXa, whereas the high selectivity for fXa versus thrombin was maintained or enhanced. Compounds 3b, 3c, 3e, and 4b are considered to be potential lead compounds for the development of orally active anticoagulant drugs because they demonstrated potent activity when administered orally to cynomolgus monkeys.
Sagi
Kazuyuki
K
Pharmaceutical Research Laboratories, Ajinomoto Company Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi 210-8681, Japan.
Nakagawa
Tadakiyo
T
Yamanashi
Masahiro
M
Makino
Shingo
S
Takahashi
Mitsuo
M
Takayanagi
Masaru
M
Takenaka
Kaoru
K
Suzuki
Nobuyasu
N
Oono
Seiji
S
Kataoka
Noriyasu
N
Ishikawa
Kohki
K
Shima
Sayaka
S
Fukuda
Yumiko
Y
Kayahara
Takashi
T
Takehana
Shunji
S
Shima
Yoichiro
Y
Tashiro
Kazumi
K
Yamamoto
Hiroshi
H
Yoshimoto
Ryota
R
Iwata
Seinosuke
S
Tsuji
Takashi
T
Sakurai
Kuniya
K
Shoji
Masataka
M
D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D011422:Propionates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019289:Pyruvic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry
D000578:Amidines; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011422:Propionates; D019289:Pyruvic Acid; D013917:Thrombin; D015951:Factor Xa