1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as potent factor Xa inhibitors.: Part 3:: Design, synthesis and SAR of orally bioavailable benzamidine-P4 inhibitors

被引：55

作者：

Jia, ZZ ^{[1
]}

Wu, YH ^{[1
]}

Huang, WR ^{[1
]}

Zhang, PL ^{[1
]}

Song, YH ^{[1
]}

Woolfrey, J ^{[1
]}

Sinha, U ^{[1
]}

Arfsten, AE ^{[1
]}

Edwards, ST ^{[1
]}

Hutchaleelaha, A ^{[1
]}

Hollennbach, SJ ^{[1
]}

Lambing, JL ^{[1
]}

Scarborough, RM ^{[1
]}

Zhu, BY ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 05期

关键词：

factor Xa inhibitors;

D O I：

10.1016/j.bmcl.2003.12.054

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using N,N-dialkylated benzamidines as the novel P4 motifs, we have designed and synthesized a class of 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as highly potent and selective fXa inhibitors with significantly improved hydrophilicity and in vitro anticoagulant activity. These benzamidine-P4 fXa inhibitors have displayed excellent oral bioavailability and long half-life. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：1229 / 1234

页数：6

共 17 条

[1] GPIIb/IIIa integrin antagonists with the new conformational restriction unit, trisubstituted β-amino acid derivatives, and a substituted benzamidine structure [J].

Hayashi, Y ;

Katada, J ;

Harada, T ;

Tachiki, A ;

Iijima, K ;

Takiguchi, Y ;

Muramatsu, M ;

Miyazaki, H ;

Asari, T ;

Okazaki, T ;

Sato, Y ;

Yasuda, E ;

Yano, M ;

Uno, I ;

Ojima, I .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (13) :2345-2360

[2]

HOLLENBACH S, 1994, THROMB HAEMOSTASIS, V71, P357

[3]

JIA ZJ, 2004, BIOORG MED CHEM LETT, V14

[4] Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors.: Part 1:: P1 structure-activity relationships of the substituted 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides [J].

Jia, ZZJ ;

Wu, YH ;

Huang, WR ;

Goldman, E ;

Zhang, PL ;

Woolfrey, J ;

Wong, P ;

Huang, B ;

Sinha, U ;

Park, G ;

Reed, A ;

Scarborough, RM ;

Zhu, BY .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (12) :1651-1655

[5] Development and validation of a genetic algorithm for flexible docking [J].

Jones, G ;

Willett, P ;

Glen, RC ;

Leach, AR ;

Taylor, R .

JOURNAL OF MOLECULAR BIOLOGY, 1997, 267 (03) :727-748

[6] New platelet fibrinogen receptor glycoprotein IIb-IIIa antagonists:: Orally active series of N-alkylated amidines with a 6,6-bicyclic template [J].

Okumura, K ;

Shimazaki, T ;

Aoki, Y ;

Yamashita, H ;

Tanaka, E ;

Banba, S ;

Yazawa, K ;

Kibayashi, K ;

Banno, H .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (21) :4036-4052

[7] Discovery of N-[2-[5-[amino(imino)methyl]-2-hydroxyphenoxy]-3,5-difluoro-6-[3-(4,5-dihydro-1-methyl-1H-imidazol-2-yl)phenoxy]pyridin-4-yl]-N-methylglycine (ZK-807834):: A potent, selective, and orally active inhibitor of the blood coagulation enzyme factor Xa [J].

Phillips, GB ;

Buckman, BO ;

Davey, DD ;

Eagen, KA ;

Guilford, WJ ;

Hinchman, J ;

Ho, E ;

Koovakkat, S ;

Liang, A ;

Light, DR ;

Mohan, R ;

Ng, HP ;

Post, JM ;

Shaw, KJ ;

Smith, D ;

Subramanyam, B ;

Sullivan, ME ;

Trinh, L ;

Vergona, R ;

Walters, J ;

White, K ;

Whitlow, M ;

Wu, S ;

Xu, W ;

Morrissey, MM .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (19) :3557-3562

[8] Discovery of 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2′- (methylsulfonyl)-[1,1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa [J].

Pinto, DJP ;

Orwat, MJ ;

Wang, SG ;

Fevig, JM ;

Quan, ML ;

Amparo, E ;

Cacciola, J ;

Rossi, KA ;

Alexander, RS ;

Smallwood, AM ;

Luettgen, JM ;

Liang, L ;

Aungst, BJ ;

Wright, MR ;

Knabb, RM ;

Wong, PC ;

Wexler, RR ;

Lam, PYS .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (04) :566-578

[9] Nonbenzamidine tetrazole derivatives as factor Xa inhibitors [J].

Quan, ML ;

Ellis, CD ;

He, MY ;

Liauw, AY ;

Woerner, FJ ;

Alexander, RS ;

Knabb, RM ;

Lam, PYS ;

Luettgen, JM ;

Wong, PC ;

Wright, MR ;

Wexler, RR .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (03) :369-373

[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 →