共查询到20条相似文献,搜索用时 296 毫秒
1.
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
2.
Deng JZ McMasters DR Rabbat PM Williams PD Coburn CA Yan Y Kuo LC Lewis SD Lucas BJ Krueger JA Strulovici B Vacca JP Lyle TA Burgey CS 《Bioorganic & medicinal chemistry letters》2005,15(20):4411-4416
Thrombin-inhibitor X-ray crystal structures, in combination with the installation of binding elements optimized within the pyrazinone series of thrombin inhibitors, were utilized to transform a weak triazolopyrimidine lead into a series of potent oxazolopyridines. A modification intended to attenuate plasma protein binding (i.e., conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual thrombin/factor Xa inhibitors demonstrated excellent in vitro and in vivo anticoagulant efficacy. 相似文献
3.
Protease inhibitors are useful tools for increasing the inhibitor potential of plasma. In this context, thrombin inhibitors attracted special interest. However, other clotting enzymes, especially factor Xa, are target enzymes of protease inhibitors besides thrombin. Our studies on structure-activity relationships of benzamidine derivatives resulted in selective inhibitors of thrombin and factor Xa. The use of these inhibitors enabled us to clarify whether the antithrombin activity or the anti-factor Xa activity of a compound is more efficient in anticoagulation. We assessed the concentration-dependent inhibition of the activated partial thromboplastin time by these compounds. If one correlates the inhibitor concentration, which prolonged the clotting time by 60 s, with the dissociation constants one will realize that thrombin inhibition is significantly more efficient in anticoagulation than inhibition of factor Xa. 相似文献
4.
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
5.
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(3):507-511
Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified. 相似文献
6.
Zhang P Bao L Zuckett JF Jia ZJ Woolfrey J Arfsten A Edwards S Sinha U Hutchaleelaha A Lambing JL Hollenbach SJ Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2004,14(4):989-993
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 microM. 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. 相似文献
7.
Arnaiz DO Zhao Z Liang A Trinh L Witlow M Koovakkat SK Shaw KJ 《Bioorganic & medicinal chemistry letters》2000,10(9):957-961
A series of indole and carbazole based inhibitors of factor Xa (FXa) has been investigated. The most potent compound inhibits FXa with a Ki of 0.2 nM and has 900- and 750-fold selectivity over thrombin and trypsin, respectively. 相似文献
8.
Quan ML Ellis CD He MY Liauw AY Woerner FJ Alexander RS Knabb RM Lam PY Luettgen JM Wong PC Wright MR Wexler RR 《Bioorganic & medicinal chemistry letters》2003,13(3):369-373
Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P(1) substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 (12) inhibits fXa with a K(i) value of 0.35 nM and is very selective for fXa over thrombin and trypsin. 相似文献
9.
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
10.
S Y Tamura E A Goldman P W Bergum J E Semple 《Bioorganic & medicinal chemistry letters》1999,9(17):2573-2578
Rigid benzolactam P3-P2 dipeptide mimics were designed and prepared as potential inhibitors of blood coagulation factor Xa. Methoxy substitution of the tetrahydrobenzazepinone scaffold led to potent and selective inhibitors. The synthesis and biological activities of these derivatives are reported herein. 相似文献
11.
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
12.
Vacca JP 《Current opinion in chemical biology》2000,4(4):394-400
The search for the ideal anticoagulant has spanned decades and has resulted in several strategies including the clinical use of heparin, low molecular weight heparins, and the vitamin K antagonist warfarin. Over the past five years, many groups have reported preclinical results with direct-acting thrombin inhibitors and several of these are now moving into clinical trials. In addition, many groups have disclosed the discovery of potent, orally bioavailable factor Xa inhibitors. Several of these compounds are now in early clinical trials and the results are forthcoming. 相似文献
13.
Song Y Clizbe L Bhakta C Teng W Li W Wong P Huang B Sinha U Park G Reed A Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2002,12(15):2043-2046
To overcome the low bioavailability of our substituted acrylamide P1 benzamidine factor Xa inhibitors reported previously, neutral and less basic groups were used to replace the benzamidine. As a result, a series of P1 aminoisoquinoline substituted acrylamide Xa inhibitors was identified to be potent, selective, and orally bioavailable. Modification of P4 moiety of these compounds further improved their pharmacokinetic properties. 相似文献
14.
Tamura SY Levy OE Uong TH Reiner JE Goldman EA Ho JZ Cohen CR Bergum PW Nutt RF Brunck TK Semple JE 《Bioorganic & medicinal chemistry letters》2000,10(8):745-749
A novel series of rigid P3-guanylpiperidine peptide mimics 3-14 was designed as potential factor Xa and prothrombinase inhibitors. Incorporation into a P2-gly-P1-argininal motif led to highly potent and selective inhibitors. The synthesis and biological activities of these derivatives are reported herein. 相似文献
15.
Quan ML Ellis CD He MY Liauw AY Lam PY Rossi KA Knabb RM Luettgen JM Wright MR Wong PC Wexler RR 《Bioorganic & medicinal chemistry letters》2003,13(6):1023-1028
Factor Xa (fXa) is an important serine protease in the blood coagulation cascade. Inhibition of fXa has emerged as an attractive target for potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein, we describe a series of non-benzamidine isoxazoline derivatives as fXa inhibitors. The chloroaniline group was found to be the most potent benzamidine mimic in this series. Chloroaniline 1 (ST368) has a K(i) value of 1.5 nM against fXa and is highly selective for fXa relative to thrombin and trypsin. 相似文献
16.
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
17.
Qiao JX Cheng X Smallheer JM Galemmo RA Drummond S Pinto DJ Cheney DL He K Wong PC Luettgen JM Knabb RM Wexler RR Lam PY 《Bioorganic & medicinal chemistry letters》2007,17(5):1432-1437
The synthesis, SAR, pharmacokinetic profile, and modeling studies of both monocyclic and fused pyrazoles containing substituted N-arylpiperidinyl P4 moieties that are potent and selective factor Xa inhibitors will be discussed. Fused pyrazole analog 16a, with a 2'-methylsulfonylphenyl piperidine P4 group, was shown to be the best compound in this series (FXa Ki = 0.35 nM) based on potency, selectivity, and pharmacokinetic profile. 相似文献
18.
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
19.
Starting from the achiral and potent factor Xa inhibitor 1, a new and flexible solid-phase optimisation strategy is described to reduce its cationic character. By replacing one positively charged side chain by a lipophilic substituent, a novel series of highly potent and selective achiral factor Xa inhibitors was discovered. The identified lipophilic replacements in the S4 pocket might be valuable for other approaches towards fXa inhibitors. 相似文献
20.
Zhang P Bao L Zuckett JF Goldman EA Jia ZJ Arfsten A Edwards S Sinha U Hutchaleelaha A Park G Lambing JL Hollenbach SJ Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2004,14(4):983-987
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. 相似文献