Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors with improved functional activity

被引：24

作者：

Zhang, PL ^{[1
]}

Bao, L ^{[1
]}

Zuckett, JMF ^{[1
]}

Jia, ZZJ ^{[1
]}

Woolfrey, J ^{[1
]}

Arfsten, A ^{[1
]}

Edwards, S ^{[1
]}

Sinha, U ^{[1
]}

Hutchaleelaha, A ^{[1
]}

Lambing, JL ^{[1
]}

Hollenbach, SJ ^{[1
]}

Scarborough, RM ^{[1
]}

Zhu, BY ^{[1
]}

机构：

[1] Millennium Pharmaceut Inc, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 04期

关键词：

D O I：

10.1016/j.bmcl.2003.11.080

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Compound 2 containing an aminomethylbenzoyl moiety as the S4 binding motif was synthesized in order to modulate hydrophlicity of anthranilamide-based factor Xa inhibitors with substituted biphenyl P4 groups. Structure-activity relationship studies around 2 have led to a series of potent factor Xa inhibitors which are highly active in the human plasma-based thrombin generation assay with 2XTG values less than 1 muM. Compound 55 shows strong antithrombotic activity in our rabbit deep vein thrombosis model, and also exhibits good oral bioavailability and a long half life in rats. (C) 2004 Published by Elsevier Ltd.

引用

页码：989 / 993

页数：5

共 17 条

[1]

ARNAIZ DO, 2002, BIOCHEMISTRY-US, V41, P15514

[2] Structure-activity relationships of substituted benzothiophene-anthranilamide factor Xa inhibitors [J].

Chou, YL ;

Davey, DD ;

Eagen, KA ;

Griedel, BD ;

Karanjawala, R ;

Phillips, GB ;

Sacchi, KL ;

Shaw, KJ ;

Wu, SC ;

Lentz, D ;

Liang, AM ;

Trinh, L ;

Morrissey, MM ;

Kochanny, MJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (03) :507-511

[3] Recent advances in the discovery and development of direct coagulation factor Xa inhibitors [J].

Gould, WR ;

Leadley, RJ .

CURRENT PHARMACEUTICAL DESIGN, 2003, 9 (28) :2337-2347

[4] 1,2-dibenzamidobenzene inhibitors of human factor Xa [J].

Herron, DK ;

Goodson, T ;

Wiley, MR ;

Weir, LC ;

Kyle, JA ;

Yee, YK ;

Tebbe, AL ;

Tinsley, JM ;

Mendel, D ;

Masters, JJ ;

Franciskovich, JB ;

Sawyer, JS ;

Beight, DW ;

Ratz, AM ;

Milot, G ;

Hall, SE ;

Klimkowski, VJ ;

Wikel, JH ;

Eastwood, BJ ;

Towner, RD ;

Gifford-Moore, DS ;

Craft, TJ ;

Smith, GF .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (05) :859-872

[5]

HOLLENBACH S, 1994, THROMB HAEMOSTASIS, V71, P357

[6] Non-amidine-containing 1,2-dibenzamidobenzene inhibitors of human factor Xa with potent anticoagulant and antithrombotic activity [J].

Masters, JJ ;

Franciskovich, JB ;

Tinsley, JM ;

Campbell, C ;

Campbell, JB ;

Craft, TJ ;

Froelich, LL ;

Gifford-Moore, DS ;

Hay, LA ;

Herron, DK ;

Klimkowski, VJ ;

Kurz, KD ;

Metz, JT ;

Ratz, AM ;

Shuman, RT ;

Smith, GF ;

Smith, T ;

Towner, RD ;

Wiley, MR ;

Wilson, A ;

Yee, YK .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (11) :2087-2092

[7] DIBASIC (AMIDINOARYL)PROPANOIC ACID-DERIVATIVES AS NOVEL BLOOD-COAGULATION FACTOR XA INHIBITORS [J].

NAGAHARA, T ;

YOKOYAMA, Y ;

INAMURA, K ;

KATAKURA, S ;

KOMORIYA, S ;

YAMAGUCHI, H ;

HARA, T ;

IWAMOTO, M .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (08) :1200-1207

[8] Perspectives on factor Xa inhibition [J].

Rai, R ;

Sprengeler, PA ;

Elrod, KC ;

Young, WB .

CURRENT MEDICINAL CHEMISTRY, 2001, 8 (02) :101-119

[9] Synthetic direct and indirect factor Xa inhibitors [J].

Samama, MM .

THROMBOSIS RESEARCH, 2002, 106 (03) :V267-V273

[10] Chapter 8. Anticoagulants: Inhibitors of thrombin and factor Xa [J].

Sanderson, PEJ .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 36, 2001, 36 :79-88

← 1 2 →