Design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors incorporating substituted biphenyl P4 motifs

被引：25

作者：

Zhang, PL ^{[1
]}

Bao, L ^{[1
]}

Zuckett, JMF ^{[1
]}

Goldman, EA ^{[1
]}

Jia, ZZJ ^{[1
]}

Arfsten, A ^{[1
]}

Edwards, S ^{[1
]}

Sinha, U ^{[1
]}

Hutchaleelaha, A ^{[1
]}

Park, G ^{[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.2003.11.079

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Anthranilamides 4 and 5 were designed and synthesized as selective and orally bioavailable factor Xa inhibitors. Structural modifications aimed at lowering their lipophilicity were performed at the central phenyl ring and at the S4 binding biphenyl region by incorporating water solublizing substituents. The resulting compounds (e.g., 7, 8, 14, 30a, and 32b) are highly potent in vitro, and show improved activity in human plasma-based thrombin generation assay. (C) 2004 Published by Elsevier Ltd.

引用

页码：983 / 987

页数：5

共 19 条

[1] AMIDE AND ALPHA-KETO CARBONYL INHIBITORS OF THROMBIN BASED ON ARGININE AND LYSINE - SYNTHESIS, STABILITY AND BIOLOGICAL CHARACTERIZATION [J].

BRADY, SF ;

SISKO, JT ;

STAUFFER, KJ ;

COLTON, CD ;

QIU, H ;

LEWIS, SD ;

NG, AS ;

SHAFER, JA ;

BOGUSKY, MJ ;

VEBER, DF ;

NUTT, RF .

BIOORGANIC & MEDICINAL CHEMISTRY, 1995, 3 (08) :1063-1078

[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]

HEMKER HC, 1993, THROMB HAEMOSTASIS, V70, P617

[5] 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

[6]

HUANG W, 2002, 223 ACS NAT M ORL FL

[7] THROMBIN INHIBITORS BASED ON KETONE DERIVATIVES OF ARGININE AND LYSINE [J].

JONES, DM ;

ATRASH, B ;

RYDER, H ;

TEGERNILSSON, AC ;

GYZANDER, E ;

SZELKE, M .

JOURNAL OF ENZYME INHIBITION, 1995, 9 (01) :43-60

[8] 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

[9] Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1 [J].

Quan, ML ;

Liauw, AY ;

Ellis, CD ;

Pruitt, JR ;

Carini, DJ ;

Bostrom, LL ;

Huang, PP ;

Harrison, K ;

Knabb, RM ;

Thoolen, MJ ;

Wong, PC ;

Wexler, RR .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (15) :2752-2759

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

Rai, R ;

Sprengeler, PA ;

Elrod, KC ;

Young, WB .

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

← 1 2 →