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.
Pharmaceutical Research Laboratories, Ajinomoto Company Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi 210-8681, Japan.
Kazuyuki
K
Sagi
Tadakiyo
T
Nakagawa
Masahiro
M
Yamanashi
Shingo
S
Makino
Mitsuo
M
Takahashi
Masaru
M
Takayanagi
Kaoru
K
Takenaka
Nobuyasu
N
Suzuki
Seiji
S
Oono
Noriyasu
N
Kataoka
Kohki
K
Ishikawa
Sayaka
S
Shima
Yumiko
Y
Fukuda
Takashi
T
Kayahara
Shunji
S
Takehana
Yoichiro
Y
Shima
Kazumi
K
Tashiro
Hiroshi
H
Yamamoto
Ryota
R
Yoshimoto
Seinosuke
S
Iwata
Takashi
T
Tsuji
Kuniya
K
Sakurai
Masataka
M
Shoji
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