Optimization of the β-aminoester class of factor Xa inhibitors.: Part 2:: Identification of FXV673 as a potent and selective inhibitor with excellent in vivo anticoagulant activity

被引：49

作者：

Guertin, KR ^{[1
]}

Gardner, CJ ^{[1
]}

Klein, SI ^{[1
]}

Zulli, AL ^{[1
]}

Czekaj, M ^{[1
]}

Gong, Y ^{[1
]}

Spada, AP ^{[1
]}

Cheney, DL ^{[1
]}

Maignan, S ^{[1
]}

Guilloteau, JP ^{[1
]}

Brown, KD ^{[1
]}

Colussi, DJ ^{[1
]}

Chu, V ^{[1
]}

Heran, CL ^{[1
]}

Morgan, SR ^{[1
]}

Bentley, RG ^{[1
]}

Dunwiddie, CT ^{[1
]}

Leadley, RJ ^{[1
]}

Pauls, HW ^{[1
]}

机构：

[1] Aventis Pharmaceut, Drug Innovat & Approval, Bridgewater, NJ 08807 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 12期

关键词：

D O I：

10.1016/S0960-894X(02)00213-5

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Further optimization of the beta-aminoester class of factor Xa (fXa) inhibitors is described culminating in the identification of 9c (FXV673), a potent and selective factor Xa inhibitor with excellent in vivo anticoagulant activity. An X-ray structure of FXV673 bound to human fXa is also presented. Based on its selectivity, potent in vivo activity and favorable pre-clinical safety profile, FXV673 was selected for further development and is currently undergoing clinical trials. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：1671 / 1674

页数：4

共 5 条

[1] Optimization of the β-aminoester class of factor Xa inhibitors.: Part 1:: P4 and side-chain modifications for improved in vitro potency
Czekaj, M
Klein, SI
Guertin, KR
Gardner, CJ
Zulli, AL
Pauls, HW
Spada, AP
Cheney, DL
Brown, KD
Colussi, DJ
Chu, V
Leadley, RJ
Dunwiddie, CT
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (12) : 1667 - 1670
[2] Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 2: Metabolism-directed optimization studies towards orally bioavailable derivatives
Vergne, F
Bernardelli, P
Lorthiois, E
Pham, N
Proust, E
Oliveira, C
Mafroud, AK
Ducrot, P
Wrigglesworth, R
Berlioz-Seux, F
Coleon, F
Chevalier, E
Moreau, F
Idrissi, M
Tertre, A
Descours, A
Berna, P
Li, M
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (18) : 4615 - 4621
[3] Synthesis, structure -: Activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors.: 1.: Thiazolone and oxazolone series
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Connor, DT
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Sorenson, RJ
Sercel, AD
Unangst, PC
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Chan, K
Schrier, DJ
Guglietta, A
Bornemeier, DA
Dyer, RD
JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (07) : 1151 - 1160
[4] Synthesis, structure -: Activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors.: 2.: 1,3,4- and 1,2,4-thiadiazole series
Song, YT
Connor, DT
Sercel, AD
Sorenson, RJ
Doubleday, R
Unangst, PC
Roth, BD
Beylin, VG
Gilbertsen, RB
Chan, K
Schrier, DJ
Guglietta, A
Bornemeier, DA
Dyer, RD
JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (07) : 1161 - 1169
[5] Design and optimization of coagulation factor XIa inhibitors: Discovery of trans-N-((S)-1-(4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl)-2-phenylethyl)-4-(aminomethyl)cyclohexane-carboxamide, a potent factor XIa inhibitor with in vivo antithrombotic activity
Hangeland, Jon J.
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Smallheer, Joanne M.
Wang, Cailan
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Fang, Tianan
Corte, James R.
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Watson, Carol A.
Zhang, Ge
Wei, Anzhi
Morin, Paul F.
Bisacchi, Gregory S.
Seiffert, Dietmar A.
Wexler, Ruth R.
Quan, Mimi L.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2014, 247

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