共查询到20条相似文献,搜索用时 31 毫秒
1.
Mederski WW Dorsch D Anzali S Gleitz J Cezanne B Tsaklakidis C 《Bioorganic & medicinal chemistry letters》2004,14(14):3763-3769
Neutral weak halothiophene benzimidazole inhibitors of the serine protease factor Xa were identified via screening of a compound library. The X-ray crystal structure of representative 3a bound to human fXa confirmed the S1 binding mode. Starting from 3a a series of halothiophene benzimidazoles was synthesized and investigated for their factor Xa inhibitory activity. This led to potent and selective achiral inhibitors against fXa such as compounds 9k and 9w. 相似文献
2.
Nazaré M Matter H Klingler O Al-Obeidi F Schreuder H Zoller G Czech J Lorenz M Dudda A Peyman A Nestler HP Urmann M Bauer A Laux V Wehner V Will DW 《Bioorganic & medicinal chemistry letters》2004,14(11):2801-2805
A series of novel, highly potent, achiral factor Xa inhibitors based on a benzoic acid scaffold and containing a chlorophenethyl moiety directed towards the protease S1 pocket is described. A number of structural features, such as the requirements of the P1, P4 and ester-binding pocket ligands were explored with respect to inhibition of factor Xa. Compound 46 was found to be the most potent compound in a series of antithrombotic secondary assays. 相似文献
3.
Gong Y Pauls HW Spada AP Czekaj M Liang G Chu V Colussi DJ Brown KD Gao J 《Bioorganic & medicinal chemistry letters》2000,10(3):217-221
The design, synthesis and SAR of amido-(propyl and allyl)-hydroxybenzamidine coagulation factor Xa inhibitors is described. These achiral inhibitors are selective for fXa vis a vis structurally related serine proteases and are readily prepared in 6-7 linear steps. The most potent member 9j (fXa Ki = 0.75 nM) is selective (>1000-fold) and an effective anticoagulant in mammalian plasma. 相似文献
4.
Fevig JM Cacciola J Buriak J Rossi KA Knabb RM Luettgen JM Wong PC Bai SA Wexler RR Lam PY 《Bioorganic & medicinal chemistry letters》2006,16(14):3755-3760
5.
Quan ML Han Q Fevig JM Lam PY Bai S Knabb RM Luettgen JM Wong PC Wexler RR 《Bioorganic & medicinal chemistry letters》2006,16(7):1795-1798
We have previously reported on a series of aminobenzisoxazoles as potent, selective, and orally bioavailable factor Xa inhibitors, which culminated in the discovery of razaxaban. Herein, we describe another approach to improve factor Xa inhibitory potency and pharmacokinetic profile by incorporating basic and water soluble functionalities on the terminal ring of the P4 biaryl group found in our earlier Xa inhibitors. This approach resulted in a series of potent, selective, and orally bioavailable factor Xa inhibitors. 相似文献
6.
Dönnecke D Schweinitz A Stürzebecher A Steinmetzer P Schuster M Stürzebecher U Nicklisch S Stürzebecher J Steinmetzer T 《Bioorganic & medicinal chemistry letters》2007,17(12):3322-3329
Highly potent and selective substrate analogue factor Xa inhibitors were obtained by incorporation of non-basic or modestly basic P1 residues known from the development of thrombin inhibitors. The modification of the P2 and P3 amino acids strongly influenced the selectivity and provided potent dual factor Xa and thrombin inhibitors without affecting the fibrinolytic enzymes. Several inhibitors demonstrated excellent anticoagulant efficacy in standard clotting assays in human plasma. 相似文献
7.
Huang W Naughton MA Yang H Su T Dam S Wong PW Arfsten A Edwards S Sinha U Hollenbach S Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2003,13(4):723-728
A series of novel transition state factor Xa inhibitors containing a variety of lactam ring systems as central templates was synthesized in an expedient manner and allowed for a great deal of structural variability. Among them, the piperazinone-based inhibitors were found to be not only active against factor Xa but also selective over thrombin. Optimization of the P4 moiety yielded several potent compounds with IC(50) below 1 nM against factor Xa. 相似文献
8.
J M Fevig J Buriak P F Stouten R M Knabb G N Lam P C Wong R R Wexler 《Bioorganic & medicinal chemistry letters》1999,9(8):1195-1200
The serine protease factor Xa is a critical enzyme in the blood coagulation cascade. Recently, the inhibition of factor Xa has begun to emerge as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe pyrrolidine and isoxazolidine benzamidines as novel and potent inhibitors of factor Xa. 相似文献
9.
10.
Nazaré M Essrich M Will DW Matter H Ritter K Urmann M Bauer A Schreuder H Czech J Lorenz M Laux V Wehner V 《Bioorganic & medicinal chemistry letters》2004,14(16):4197-4201
A series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for P4 ligands in combination with a neutral biaryl P1 ligand were investigated with the 2-carboxyindole scaffold. A diverse set of P4 substituents was identified, which, in conjunction with a biaryl P1 ligand, gave highly potent factor Xa inhibitors, which were also selective versus other proteases and efficacious in various antithrombotic secondary assays. 相似文献
11.
Fevig JM Pinto DJ Han Q Quan ML Pruitt JR Jacobson IC Galemmo RA Wang S Orwat MJ Bostrom LL Knabb RM Wong PC Lam PYS Wexler RR 《Bioorganic & medicinal chemistry letters》2001,11(5):641-645
The selective inhibition of coagulation factor Xa has emerged as an attractive strategy for the discovery of novel antithrombotic agents. Here we describe highly potent benzamidine factor Xa inhibitors based on a vicinally-substituted heterocyclic core. 相似文献
12.
Nazaré M Essrich M Will DW Matter H Ritter K Urmann M Bauer A Schreuder H Dudda A Czech J Lorenz M Laux V Wehner V 《Bioorganic & medicinal chemistry letters》2004,14(16):4191-4195
A series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for neutral ligands, which bind in the S1 pocket of factor Xa were investigated with the 2-carboxyindole scaffold. This privileged fragment assembly approach yielded a set of equipotent, selective inhibitors with structurally diverse neutral P1 substituents. 相似文献
13.
Huang W Zhang P Zuckett JF Wang L Woolfrey J Song Y Jia ZJ Clizbe LA Su T Tran K Huang B Wong P Sinha U Park G Reed A Malinowski J Hollenbach SJ Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2003,13(3):561-566
A series of benzoxazinone derivatives was designed and synthesized as factor Xa inhibitors. We demonstrated that the naphthyl moiety in the aniline-based compounds 1 and 2 can be replaced with benzene-fused heterobicycles and biaryls to give factor Xa inhibitors with improved trypsin selectivity. The P4 modifications lead to monoamidines which are moderately active. The benzoxazinones 41-45 are potent against factor Xa, retain the improved trypsin selectivity of the corresponding aniline-based compounds, and show strong antithrombotic effect dose responsively. 相似文献
14.
Nar H Bauer M Schmid A Stassen JM Wienen W Priepke HW Kauffmann IK Ries UJ Hauel NH 《Structure (London, England : 1993)》2001,9(1):29-37
BACKGROUND: A major current focus of pharmaceutical research is the development of selective inhibitors of the blood coagulation enzymes thrombin or factor Xa to be used as orally bioavailable anticoagulant drugs in thromboembolic disorders and in the prevention of venous and arterial thrombosis. Simultaneous direct inhibition of thrombin and factor Xa by synthetic proteinase inhibitors as a novel approach to antithrombotic therapy could result in potent anticoagulants with improved pharmacological properties. RESULTS: The binding mode of such dual specific inhibitors of thrombin and factor Xa was determined for the first time by comparative crystallography using human alpha-thrombin, human des-Gla (1--44) factor Xa and bovine trypsin as the ligand receptors. The benzamidine-based inhibitors utilize two different conformations for the interaction with thrombin and factor Xa/trypsin, which are evoked by the steric requirements of the topologically different S2 subsites of the enzymes. Compared to the unliganded forms of the proteinases, ligand binding induces conformational adjustments of thrombin and factor Xa active site residues indicative of a pronounced induced fit mechanism. CONCLUSION: The structural data reveal the molecular basis for a desired unselective inhibition of the two key components of the blood coagulation cascade. The 4-(1-methyl-benzimidazole-2-yl)-methylamino-benzamidine moieties of the inhibitors are able to fill both the small solvent accessible as well as the larger hydrophobic S2 pockets of factor Xa and thrombin, respectively. Distal fragments of the inhibitors are identified which fit into both the cation hole/aromatic box of factor Xa and the hydrophobic aryl binding site of thrombin. Thus, binding constants in the medium-to-low nanomolar range are obtained against both enzymes. 相似文献
15.
Jia ZJ Wu Y Huang W Goldman E Zhang P 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
Based on DuPont Pharmaceuticals' monobenzamidine lead structure SN429, we have designed the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as a novel series of non-basic factor Xa inhibitors. We have discovered that the displacement of the benzamidine moiety with substituted 2-naphthyl structures not only results in highly potent factor Xa inhibitors, but also significantly increases their enzyme specificity and oral bioavailability. 相似文献
16.
Guertin KR Gardner CJ Klein SI Zulli AL Czekaj M Gong Y Spada AP Cheney DL Maignan S Guilloteau JP Brown KD Colussi DJ Chu V Heran CL Morgan SR Bentley RG Dunwiddie CT Leadley RJ Pauls HW 《Bioorganic & medicinal chemistry letters》2002,12(12):1671-1674
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. 相似文献
17.
Jones SD Liebeschuetz JW Morgan PJ Murray CW Rimmer AD Roscoe JM Waszkowycz B Welsh PM Wylie WA Young SC Martin H Mahler J Brady L Wilkinson K 《Bioorganic & medicinal chemistry letters》2001,11(5):733-736
Factor Xa, a critical serine protease in the blood coagulation cascade, has become a target for inhibition as a strategy for the invention of novel anti-thrombotic agents. Here we describe the development of phenylglycine containing benzamidine carboxamides as novel, potent and selective inhibitors of factor Xa. 相似文献
18.
R Rai A Kolesnikov Y Li W B Young E Leahy P A Sprengeler E Verner W D Shrader J Burgess-Henry J C Sangalang D Allen X Chen B A Katz C Luong K Elrod L Cregar 《Bioorganic & medicinal chemistry letters》2001,11(14):1797-1800
The development of potent and selective small molecule inhibitors of factor Xa is described. 相似文献
19.
Banke IJ Arlt MJ Pennington C Kopitz C Steinmetzer T Schweinitz A Gansbacher B Quigley JP Edwards DR Stürzebecher J Krüger A 《Biological chemistry》2003,384(10-11):1515-1525
Although tumors frequently show elevated protease activities, the concept of anti-proteolytic cancer therapy has lost momentum after failure of clinical trials with broad-spectrum matrix metalloproteinase inhibitors. Thus we need to adapt our design strategies for protease inhibitors. Here, we employed a series of seven structurally fine-modulated and pharmacokinetically closely related synthetic 4-amidinobenzylamine-based inhibitors with distinct selectivity for prototypical serine proteases in a murine T cell lymphoma liver metastasis model. This in vivo screening revealed efficacy of urokinase inhibitors but no correlation between urokinase selectivity or affinity and anti-metastatic effect. In contrast, factor Xa-selective inhibitors were more potent, demonstrating factor Xa or a factor Xa-like serine protease likely to be more determinant in this model. Factor Xa selectivity, but not affinity, significantly improved anti-metastatic efficacy. For example, factor Xa inhibitors CJ-504 and CJ-510 exert similar affinity for factor Xa (K(i)=14 nM versus 8.8 nM) but CJ-504 was 70-fold more selective for factor Xa. This correlated with higher anti-metastatic efficacy (58.8% with CJ-504; 28.2% with CJ-510). Our results show that among the protease inhibitors employed that have affinities in the nanomolar range, the strategy of selectivity-optimization is superior to further improvement of affinity to significantly enhance anti-metastatic efficacy. This appreciation may be important for the future rational design of new anti-proteolytic agents for cancer therapy. 相似文献
20.
Marlowe CK Sinha U Gunn AC Scarborough RM 《Bioorganic & medicinal chemistry letters》2000,10(1):13-16
A series of arginine aldehyde inhibitors was designed as transition state (TS) analogues based on the known factor Xa specific substrate Cbz-D-Arg-Gly-Arg-pNA. BnSO2-(D)Arg-Gly-Arg-H (20) was found to be the most potent and selective inhibitor of factor Xa and prothrombinase activity in this series. 相似文献