Factor VIIa inhibitors: Target hopping in the serine protease family using X-ray structure determination

被引：13

作者：

Shiraishi, Takuya ^{[1
]}

Kadono, Shojiro ^{[1
]}

Haramura, Masayuki ^{[1
]}

Kodama, Hirofumi ^{[1
]}

Ono, Yoshiyuki ^{[1
]}

Iikura, Hitoshi ^{[1
]}

Esaki, Tohru ^{[1
]}

Koga, Takaki ^{[1
]}

Hattori, Kunihiro ^{[1
]}

Watanabe, Yoshiaki ^{[1
]}

Sakamoto, Akihisa ^{[1
]}

Yoshihashi, Kazutaka ^{[1
]}

Kitazawa, Takehisa ^{[1
]}

Esaki, Keiko ^{[1
]}

Ohta, Masateru ^{[1
]}

Sato, Haruhiko ^{[1
]}

Kozono, Toshiro ^{[1
]}

机构：

[1] Chugai Pharmaceut Co Ltd, Fuji Gotemba Res Labs, Shizuoka 4128513, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 16期

关键词：

factor VIIa; thromboembolic disorder; serine protease; thrombin; X-ray; peptidemimetic inhibitor;

D O I：

10.1016/j.bmcl.2008.07.044

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4533 / 4537

页数：5

共 38 条

[1] BANNER DW, 1991, J BIOL CHEM, V266, P20085
[2] The crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor
Banner, DW
DArcy, A
Chene, C
Winkler, FK
Guha, A
Konigsberg, WH
Nemerson, Y
Kirchhofer, D
[J]. NATURE, 1996, 380 (6569) : 41 - 46
[3] THE REFINED 1.9 A CRYSTAL-STRUCTURE OF HUMAN ALPHA-THROMBIN - INTERACTION WITH D-PHE-PRO-ARG CHLOROMETHYLKETONE AND SIGNIFICANCE OF THE TYR-PRO-PRO-TRP INSERTION SEGMENT
BODE, W
MAYR, I
BAUMANN, U
HUBER, R
STONE, SR
HOFSTEENGE, J
[J]. EMBO JOURNAL, 1989, 8 (11) : 3467 - 3475
[4] BODE W, 1992, PROTEIN SCI, V1, P426
[5] Redefining medical treatment in the management of unstable angina
Braunwald, E
Califf, RM
Cannon, CP
Fox, KAA
Fuster, V
Gibler, WB
Harrington, RA
King, SB
Kleiman, NS
Theroux, P
Topol, EJ
Van de Werf, F
White, HD
Willerson, JT
[J]. AMERICAN JOURNAL OF MEDICINE, 2000, 108 (01) : 41 - 53
[6] THE COAGULATION CASCADE - INITIATION, MAINTENANCE, AND REGULATION
DAVIE, EW
FUJIKAWA, K
KISIEL, W
[J]. BIOCHEMISTRY, 1991, 30 (43) : 10363 - 10370
[7] On the calculation of binding free energies using continuum methods: Application to MHC class I protein-peptide interactions
Froloff, N
Windemuth, A
Honig, B
[J]. PROTEIN SCIENCE, 1997, 6 (06) : 1293 - 1301
[8] Haas S, 2007, Hamostaseologie, V27, P41
[9] Harker LA, 1996, HAEMOSTASIS, V26, P76
[10] HENDSCH ZS, 1994, PROTEIN SCI, V3, P211

← 1 2 3 4 →