446845-66-5Relevant academic research and scientific papers
Design and synthesis of peptidomimetic factor VIIa inhibitors
Shiraishi, Takuya,Kadono, Shojiro,Haramura, Masayuki,Kodama, Hirofumi,Ono, Yoshiyuki,Iikura, Hitoshi,Esaki, Tohru,Koga, Takaki,Hattori, Kunihiro,Watanabe, Yoshiaki,Sakamoto, Akihisa,Yoshihashi, Kazutaka,Kitazawa, Takehisa,Esaki, Keiko,Ohta, Masateru,Sato, Haruhiko,Kozono, Toshiro
, p. 38 - 44 (2010)
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. In previous reports, we described a S3 subsite found in the X-ray crystal structure of compound 2 that bound to FVIIa/soluble tissue factor (sTF). Based on the X-ray crystal structure information and with the aim of improving the inhibition activity for FVIIa/TF and selectivity against other serine proteases, we synthesized derivatives by introducing substituents at position 5 of the indole ring of compound 2. Among them, compound 16 showed high selectivity against other serine proteases. Contrary to our expectations, compound 16 did not occupy the S3-subsite; X-ray structure analysis revealed that compound 16 improved selectivity by forming hydrogen bonds with Gln217, Thr99 and Asn100.
Factor VIIa inhibitors: Target hopping in the serine protease family using X-ray structure determination
Shiraishi, Takuya,Kadono, Shojiro,Haramura, Masayuki,Kodama, Hirofumi,Ono, Yoshiyuki,Iikura, Hitoshi,Esaki, Tohru,Koga, Takaki,Hattori, Kunihiro,Watanabe, Yoshiaki,Sakamoto, Akihisa,Yoshihashi, Kazutaka,Kitazawa, Takehisa,Esaki, Keiko,Ohta, Masateru,Sato, Haruhiko,Kozono, Toshiro
scheme or table, p. 4533 - 4537 (2009/04/08)
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. Compound 1 was discovered from focused screening of serine protease-directed compounds from our internal collection. Using parallel synthesis supported by structure-based drug design, we identified peptidemimetic FVIIa/TF inhibitors (compounds 4-11) containing l-Gln or l-Met as the P2 moiety. However, these compounds lacked the selectivity of other serine proteases in the coagulation cascade, especially thrombin. Further optimization of these compounds was carried out with a focus on the P4 moiety. Among the optimized compounds, 12b-f showed improved selectivity.
