共查询到20条相似文献,搜索用时 15 毫秒
1.
Kochanny MJ Adler M Ewing J Griedel BD Ho E Karanjawala R Lee W Lentz D Liang AM Morrissey MM Phillips GB Post J Sacchi KL Sakata ST Subramanyam B Vergona R Walters J White KA Whitlow M Ye B Zhao Z Shaw KJ 《Bioorganic & medicinal chemistry》2007,15(5):2127-2146
A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa. 相似文献
2.
Song Y Clizbe L Bhakta C Teng W Li W Wu Y Jia ZJ Zhang P Wang L Doughan B Su T Kanter J Woolfrey J Wong P Huang B Tran K Sinha U Park G Reed A Malinowski J Hollenbach S Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2002,12(11):1511-1515
Substituted acrylamides were used as templates that bridge P1 and P4 binding elements, resulting in a series of potent (sub-nanomolar) and selective factor Xa inhibitors. In this template, cis-geometry of P1 and P4 ligands is highly preferred. SAR on the substituting groups, as well as on modification of P1 and P4 moieties is described. Compounds in this series show good in vivo efficacy in animal models. 相似文献
3.
Mederski WW Cezanne B van Amsterdam C Bühring KU Dorsch D Gleitz J März J Tsaklakidis C 《Bioorganic & medicinal chemistry letters》2004,14(23):5817-5822
Neutral chlorothiophenecarboxamides bearing an amino acid and a substituted aniline were synthesized and investigated for their factor Xa inhibitory activity in vitro. From selected 2-methylphenyl morpholinones the solution properties were determined. The most soluble and active compounds were then investigated in different animal species to compare the pharmacokinetic parameters. This led to a potent, water soluble and orally bioavailable candidate for further development: EMD 495235. 相似文献
4.
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
5.
Mimi L. Quan Donald J.P. Pinto Karen A. Rossi Steven Sheriff Richard S. Alexander Eugene Amparo Kevin Kish Robert M. Knabb Joseph M. Luettgen Paul Morin Angela Smallwood Francis J. Woerner Ruth R. Wexler 《Bioorganic & medicinal chemistry letters》2010,20(4):1373-1377
We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate. 相似文献
6.
Komoriya S Kobayashi S Osanai K Yoshino T Nagata T Haginoya N Nakamoto Y Mochizuki A Nagahara T Suzuki M Shimada T Watanabe K Isobe Y Furugoori T 《Bioorganic & medicinal chemistry》2006,14(5):1309-1330
Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity. 相似文献
7.
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
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.
Pruitt JR Pinto DJ Estrella MJ Bostrom LL Knabb RM Wong PC Wright MR Wexler RR 《Bioorganic & medicinal chemistry letters》2000,10(8):685-689
3,4,5-Trisubstituted isoxazolines (2) and isoxazoles (3) were prepared and evaluated for their in vitro and in vivo antithrombotic efficacy. They were compared to 3,5,5-trisubstituted isoxazolines (1) for Factor Xa selectivity and potency. They were also compared in an arterio-venous (A-V) shunt model of thrombosis. 相似文献
10.
11.
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
12.
Penglie Zhang Liang Bao Jingmei Fan Zhaozhong J. Jia Uma Sinha Paul W. Wong Gary Park Athiwat Hutchaleelaha Robert M. Scarborough Bing-Yan Zhu 《Bioorganic & medicinal chemistry letters》2009,19(8):2186-2189
Anthranilamide-based benzamidine compound 4 and its N-substituted analogs were designed and examined as factor Xa inhibitors using substituted benzamidines as unconventional S4 binding element. A group of N,N-dialkylbenzamidines (11, 17 and 24) have been discovered as potent factor Xa inhibitors with strong anticoagulant activity and promising oral PK profiles. 相似文献
13.
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
14.
Nagata T Yoshino T Haginoya N Yoshikawa K Isobe Y Furugohri T Kanno H 《Bioorganic & medicinal chemistry letters》2007,17(16):4683-4688
This paper describes the synthesis of orally available potent fXa inhibitors 2 and 3 by modification of the piperazine part of lead compound 1. Carbonyl derivative 3 showed potent fXa activity but not sulfonyl derivative 2. Among the compounds synthesized, cyclohexane derivatives 3g and 3h and cycloheptane derivative 3j had potent anticoagulant activity as well as anti-fXa activity. Synthetic study of the optical isomers of 3g demonstrated that (-)-3g had more potent activity. 相似文献
15.
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
16.
《Bioorganic & medicinal chemistry letters》2014,24(15):3341-3345
In an effort to identify a potential back-up to apixaban (Eliquis®), we explored a series of diversified P4 moieties. Several analogs with substituted gem-dimethyl moieties replacing the terminal lactam of apixaban were identified which demonstrated potent FXa binding affinity (FXa Ki), good human plasma anticoagulant activity (PT EC2x), cell permeability, and oral bioavailability. 相似文献
17.
Gong Y Becker M Choi-Sledeski YM Davis RS Salvino JM Chu V Brown KD Pauls HW 《Bioorganic & medicinal chemistry letters》2000,10(10):1033-1036
A focused library (4 x 14) prepared from 4-aminopyridine and 4-, 5-, and 6-azoindole templates was synthesized using 14 polymer supported 4-amido-2,3,5,6-tetrafluorophenyl (TFP) sulfonate esters inputs. Several compounds were identified as factor Xa inhibitors (IC50< or =0.1 microM) helping to establish the SAR among these four series of azarene pyrrolidinones. 相似文献
18.
Shi Y O'Connor SP Sitkoff D Zhang J Shi M Bisaha SN Wang Y Li C Ruan Z Lawrence RM Klei HE Kish K Liu EC Seiler SM Schweizer L Steinbacher TE Schumacher WA Robl JA Macor JE Atwal KS Stein PD 《Bioorganic & medicinal chemistry letters》2011,21(24):7516-7521
The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide–valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC50 of 7 nM and EC2×PT of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide–valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets. 相似文献
19.
Smallheer JM Wang S Laws ML Nakajima S Hu Z Han W Jacobson I Luettgen JM Rossi KA Rendina AR Knabb RM Wexler RR Lam PY Quan ML 《Bioorganic & medicinal chemistry letters》2008,18(7):2428-2433
As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties. 相似文献
20.
Franciskovich JB Masters JJ Tinsley JM Craft TJ Froelich LL Gifford-Moore DS Klimkowski VJ Smallwood JK Smith GF Smith T Towner RR Weir LC Wiley MR 《Bioorganic & medicinal chemistry letters》2005,15(21):4838-4841
Several non-amidino S1 derivatives of the 1,2-diaminobenzene-based scaffold (4) were synthesized and evaluated for their ability to bind to the active site and inhibit the human protease factor Xa. A subset of these compounds were also evaluated for their anticoagulant effects in human plasma as measured by prothrombin time (PT). 相似文献