共查询到20条相似文献,搜索用时 312 毫秒
1.
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
2.
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
3.
Young RJ Campbell M Borthwick AD Brown D Burns-Kurtis CL Chan C Convery MA Crowe MC Dayal S Diallo H Kelly HA King NP Kleanthous S Mason AM Mordaunt JE Patel C Pateman AJ Senger S Shah GP Smith PW Watson NS Weston HE Zhou P 《Bioorganic & medicinal chemistry letters》2006,16(23):5953-5957
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties. 相似文献
4.
Mendel D Marquart AL Joseph S Waid P Yee YK Tebbe AL Ratz AM Herron DK Goodson T Masters JJ Franciskovich JB Tinsley JM Wiley MR Weir LC Kyle JA Klimkowski VJ Smith GF Towner RD Froelich LL Buben J Craft TJ 《Bioorganic & medicinal chemistry letters》2007,17(17):4832-4836
SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays. 相似文献
5.
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
6.
Varnes JG Wacker DA Pinto DJ Orwat MJ Theroff JP Wells B Galemo RA Luettgen JM Knabb RM Bai S He K Lam PY Wexler RR 《Bioorganic & medicinal chemistry letters》2008,18(2):749-754
Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin. 相似文献
7.
Watson NS Brown D Campbell M Chan C Chaudry L Convery MA Fenwick R Hamblin JN Haslam C Kelly HA King NP Kurtis CL Leach AR Manchee GR Mason AM Mitchell C Patel C Patel VK Senger S Shah GP Weston HE Whitworth C Young RJ 《Bioorganic & medicinal chemistry letters》2006,16(14):3784-3788
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species. 相似文献
8.
Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs
Young RJ Borthwick AD Brown D Burns-Kurtis CL Campbell M Chan C Charbaut M Chung CW Convery MA Kelly HA Paul King N Kleanthous S Mason AM Pateman AJ Patikis AN Pinto IL Pollard DR Senger S Shah GP Toomey JR Watson NS Weston HE 《Bioorganic & medicinal chemistry letters》2008,18(1):23-27
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities. 相似文献
9.
Young RJ Borthwick AD Brown D Burns-Kurtis CL Campbell M Chan C Charbaut M Convery MA Diallo H Hortense E Irving WR Kelly HA King NP Kleanthous S Mason AM Pateman AJ Patikis AN Pinto IL Pollard DR Senger S Shah GP Toomey JR Watson NS Weston HE Zhou P 《Bioorganic & medicinal chemistry letters》2008,18(1):28-33
Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles. 相似文献
10.
Komoriya S Kanaya N Nagahara T Yokoyama A Inamura K Yokoyama Y Katakura S Hara T 《Bioorganic & medicinal chemistry》2004,12(9):2099-2114
Since factor Xa (fXa) plays a pivotal role in the blood coagulation cascade, inhibition of fXa is thought to be an effective treatment for a variety of thrombotic events. (2S)-2-[4-[[(3S)-1-Acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (DX-9065a) was previously found in our laboratory as a novel orally active factor Xa inhibitor. DX-9065a exhibits a strong inhibitory activity toward fXa by occupying the substrate recognition (called S1) sites and aryl binding sites of fXa. Herein we describe conversions of the amidinonaphthalene and the acetimidoylpyrrolidine moieties of DX-9065a. Some compounds showed remarkably increased in vitro anti-factor Xa and PRCT activities compared with those of DX-9065a. The most promising compound 38 showed four times the prolongation of APTT against DX-9065a after oral administration to rats. 相似文献
11.
Pinto DJ Orwat MJ Quan ML Han Q Galemmo RA Amparo E Wells B Ellis C He MY Alexander RS Rossi KA Smallwood A Wong PC Luettgen JM Rendina AR Knabb RM Mersinger L Kettner C Bai S He K Wexler RR Lam PY 《Bioorganic & medicinal chemistry letters》2006,16(15):4141-4147
Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa. 相似文献
12.
Cook BC Rudolph AE Kurumbail RG Porche-Sorbet R Miletich JP 《The Journal of biological chemistry》2000,275(49):38774-38779
Based on homology, amino acids 326-336 (143-154 in chymotrypsin numbering) of factor X (fX) comprise a flexible surface loop, which is susceptible to self-proteolysis and influences substrate catalysis. To investigate the role of this autolysis loop in fX function, a recombinant variant with a new site for asparagine-linked glycosylation has been produced by changing glutamine 333 to asparagine. Q333N fX is activated normally by factor VIIa and tissue factor, factors IXa and VIIIa, and Russell's viper venom. Proteolysis of the loop is prevented by the mutation. Reactivity of the free enzyme toward substrates and inhibitors is attenuated 4-20-fold; relative to wild type fXa, Spectrozyme Xa(TM) hydrolysis is 25%, inhibition by antithrombin III and the tissue factor pathway inhibitor is approximately 20%, and prothrombin activation in the absence of the cofactor Va is only 5%. Surprisingly, activities of the variant and wild type enzymes are equivalent when part of the prothrombinase complex. N-Glycanase cleaves the new oligosaccharide from Q333N fXa leaving aspartic acid. Q333D fXa is approximately 1.6-fold more reactive with Spectrozyme Xa(TM), antithrombin III and tissue factor pathway inhibitor, and prothrombin than its glycosylated counterpart, Q333N fXa, but still quite abnormal relative to wild type fXa. Like Q333N fXa, Q333D fXa is fully functional as part of the prothrombinase complex. We conclude that Gln-333 is geographically close to a site of proteolytic degradation but not to activator, cofactor, or membrane binding sites. Mutation of Gln-333 impairs catalytic function, but given normal prothrombin activation by the complexed enzyme, the importance of Gln-333 for catalysis is not manifest in the prothrombinase assembly, suggesting a conformational change in complexed fXa. 相似文献
13.
M R Becker W R Ewing R S Davis H W Pauls C Ly A Li H J Mason Y M Choi-Sledeski A P Spada V Chu K D Brown D J Colussi R J Leadley R Bentley J Bostwick C Kasiewski S Morgan 《Bioorganic & medicinal chemistry letters》1999,9(18):2753-2758
Thienopyridine sulfonamide pyrrolidinones were found to be potent and selective inhibitors of the coagulation cascade enzyme factor Xa. SAR studies led to several compounds that were selected for further in vivo investigation. These novel aryl binding pocket moieties represent a structural modification to a series of fXa inhibitors. Several compounds proved to be efficacious i.v. antithrombotic agents. 相似文献
14.
Nagashima H 《The Journal of biological chemistry》2002,277(52):50439-50444
The present study began with mathematical modeling of how inhibitors of both factor Xa (fXa) and thrombin affect extrinsic pathway-triggered blood coagulation. Numerical simulation demonstrated a stronger inhibition of thrombin generation by a thrombin inhibitor than a fXa inhibitor, but both prolonged clot time to a similar extent when they were given an equal dissociation constant (30 nm) for interaction with their respective target enzymes. These differences were then tested by comparison with the real inhibitors DX-9065a and argatroban, specific competitive inhibitors of fXa and thrombin, respectively, with similar K(i) values. Comparisons were made in extrinsically triggered human citrated plasma, for which endogenous thrombin potential and clot formation were simultaneously measured with a Wallac multilabel counter equipped with both fluorometric and photometric detectors and a fluorogenic reporter substrate. The results demonstrated stronger inhibition of endogenous thrombin potential by argatroban than by DX-9065a, especially when coagulation was initiated at higher tissue factor concentrations, while argatroban appeared to be slightly less potent in its ability to prolong clot time. This study demonstrates differential inhibition of thrombin generation by fXa and thrombin inhibitors and has implications for the pharmacological regulation of blood coagulation by the anticoagulant protease inhibitors. 相似文献
15.
Koshio H Hirayama F Ishihara T Taniuchi Y Sato K Sakai-Moritani Y Kaku S Kawasaki T Matsumoto Y Sakamoto S Tsukamoto S 《Bioorganic & medicinal chemistry》2004,12(9):2179-2191
Factor Xa (fXa) is a serine protease involved in the coagulation cascade, which has received great interest as a potential target for the development of new antithrombotic drugs. Herein we report a novel series of fXa inhibitors in which the 1,4-diazepane moiety was designed to interact with the S4 aryl-binding domain of the fXa active site. Compound 13 (YM-96765) showed potent fXa inhibitory activity (IC(50) = 6.8 nM) and effective antithrombotic activity without prolonging bleeding time. 相似文献
16.
Protein Z-dependent protease inhibitor (ZPI) is a plasma serpin, which can rapidly inactivate factor Xa (fXa) in the presence of protein Z (PZ), negatively charged phospholipids, and Ca2+. To investigate the mechanism by which ZPI inactivates fXa, we expressed the serpin in mammalian cells and characterized its reactivity with both wild-type and selected mutants of fXa that 1) contained substitutions in the autolysis loop and the heparin binding exosite, 2) lacked the first EGF-like domain (fXa-des-EGF-1), or 3) contained the Gla domain of protein C (fXa/PC-Gla). Inhibition studies in both the presence and absence of PZ revealed that Arg-143, Lys-147, and Arg-154 of the autolysis loop and Lys-96, Lys-169, and Lys-236 of the heparin binding exosite are required for recognition of ZPI, with Arg-143 being essential for the interaction. Similar studies with fXa-des-EGF-1 and fXa/PC-Gla suggested that protein-protein interaction with either the Gla or the EGF-1 domain may not play a dominant role in the PZ-dependent recognition of fXa by the serpin on phospholipid vesicles. Further studies showed that an inactive Ser-195 to Ala mutant of fXa effectively competes with wild-type fXa for binding to the non-serpin inhibitors tissue factor pathway inhibitor and recombinant tick anticoagulant peptide, but does not compete for binding to ZPI. This suggests that the catalytic residue of fXa is required for interaction with ZPI. 相似文献
17.
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
18.
Su T Wu Y Doughan B Kane-Maguire K Marlowe CK Kanter JP Woolfrey J Huang B Wong P Sinha U Park G Malinowski J Hollenbach S Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2001,11(17):2279-2282
A series of glycolic and mandelic acid derivatives was synthesized and investigated for their factor Xa inhibitory activity. These analogues are highly potent and selective inhibitors against fXa. In a rabbit deep vein thrombosis model, compound 26 showed significant antithrombotic effects (81% inhibition of thrombus formation) at 1.1 microM plasma concentration following intravenous administration. 相似文献
19.
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
20.
Varnes JG Wacker DA Jacobson IC Quan ML Ellis CD Rossi KA He MY Luettgen JM Knabb RM Bai S He K Lam PY Wexler RR 《Bioorganic & medicinal chemistry letters》2007,17(23):6481-6488
A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban. 相似文献