共查询到20条相似文献,搜索用时 31 毫秒
1.
Imaeda Y Miyawaki T Sakamoto H Itoh F Konishi N Hiroe K Kawamura M Tanaka T Kubo K 《Bioorganic & medicinal chemistry》2008,16(5):2243-2260
Factor Xa (FXa) is a trypsin-like serine protease involved in the coagulation cascade and has received great interest as a potential target for the development of new antithrombotic agents. Most of amidine-type FXa inhibitors reported have been found to show extremely poor oral bioavailability. Compound 1 is one of the first reported non-amidine type FXa inhibitors. To discover novel and orally active FXa inhibitors, we investigated flexible linear linkers between the 6-chloronaphthalene ring and the 1-(pyridin-4-yl)piperidine moiety of 1 and found the orally active sulfonylalkylamide 2f with an FXa IC(50) of 0.05 microM, comparable with that of 1. Further modification to reduce the CYP3A4 inhibitory activity of 2f resulted in the potent, selective, and orally active 2-methylpyridine analogue 2s (FXa IC(50) of 0.061 microM), for which the liability of CYP3A4 inhibition was significantly weakened compared to 2f. Compound 2s also showed long lasting anticoagulant activity in cynomolgus monkeys. 相似文献
2.
Kohrt JT Filipski KJ Cody WL Bigge CF La F Welch K Dahring T Bryant JW Leonard D Bolton G Narasimhan L Zhang E Peterson JT Haarer S Sahasrabudhe V Janiczek N Desiraju S Hena M Fiakpui C Saraswat N Sharma R Sun S Maiti SN Leadley R Edmunds JJ 《Bioorganic & medicinal chemistry》2006,14(13):4379-4392
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability. 相似文献
3.
Hirayama F Koshio H Ishihara T Watanuki S Hachiya S Kaizawa H Kuramochi T Katayama N Kurihara H Taniuchi Y Sato K Sakai-Moritani Y Kaku S Kawasaki T Matsumoto Y Sakamoto S Tsukamoto S 《Bioorganic & medicinal chemistry》2002,10(8):2597-2610
Factor Xa (FXa) is a serine protease which plays a pivotal role in the coagulation cascade. The inhibition of FXa has received great interest as a potential target for the development of new antithrombotic drug. Herein we describe a series of novel 7-amidino-2-naphthoanilide and 7-amidino-2-naphthalensulfonanilide derivatives which are potent FXa inhibitors. These scaffolds are rigid and are allowed to adopt an L-shape conformation which was estimated as the active conformation based on a docking study of YM-60828 with FXa. Optimization of the side chain at the central aniline nitrogen of 7-amidino-2-naphthoanilide has led to several potent and orally active FXa inhibitors. 5h (YM-169964), the best compound of these series, showed potent FXa inhibitory activity (IC(50)=3.9nM) and effectively prolonged prothrombin time by 9.6-fold ex vivo at an oral dose of 3mg/kg in squirrel monkeys. 相似文献
4.
Qiao JX Wang TC Wang GZ Cheney DL He K Rendina AR Xin B Luettgen JM Knabb RM Wexler RR Lam PY 《Bioorganic & medicinal chemistry letters》2007,17(18):5041-5048
We previously reported a series of enantiopure cis-(1R,2S)-cyclopentyldiamine derivatives as potent and selective inhibitors of Factor Xa (FXa). Herein, we describe our approach to improve the metabolic stability of this series via core modifications. Multiple resulting series of compounds demonstrated similarly high FXa potency and improved metabolic stability in human liver microsomes compared with the cyclopentyldiamide 1. (3R,4S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa K(i) of 0.50 nM, PT EC(2x) of 2.1 microM in human plasma, bioavailability of 25% and t(1/2)of 2.7h in dogs. Further biochemical characterization of compound 31 is also presented. 相似文献
5.
Hirayama F Koshio H Katayama N Ishihara T Kaizawa H Taniuchi Y Sato K Sakai-Moritani Y Kaku S Kurihara H Kawasaki T Matsumoto Y Sakamoto S Tsukamoto S 《Bioorganic & medicinal chemistry》2003,11(3):367-381
Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure-activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described. 相似文献
6.
《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
7.
Han Y Belley M Bayly CI Colucci J Dufresne C Giroux A Lau CK Leblanc Y McKay D Therien M Wilson MC Skorey K Chan CC Scapin G Kennedy BP 《Bioorganic & medicinal chemistry letters》2008,18(11):3200-3205
A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer. 相似文献
8.
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
9.
Novel, potent and selective chimeric FXa inhibitors featuring hydrophobic P1-ketoamide moieties 总被引:2,自引:0,他引:2
Semple JE Levy OE Minami NK Owens TD Siev DV 《Bioorganic & medicinal chemistry letters》2000,10(20):2305-2309
Judicious combination of P-region sequences of highly potent anticoagulant proteins including NAP5, NAP6, Ecotin, and Antistasin with SAR from small molecule FXa inhibitors led to a series of chimeric inhibitors of formula 1a-j. We report herein the design, synthesis, and biological activity of this novel family of FXa inhibitors that express both high in vitro potency and superb selectivity against related serine proteases. 相似文献
10.
Shi Y Sitkoff D Zhang J Han W Hu Z Stein PD Wang Y Kennedy LJ O'Connor SP Ahmad S Liu EC Seiler SM Lam PY Robl JA Macor JE Atwal KS Zahler R 《Bioorganic & medicinal chemistry letters》2007,17(21):5952-5958
The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.5 nM and PT EC(2x) of 1.7 microM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets. 相似文献
11.
O'Connor SP Atwal K Li C Liu EC Seiler SM Shi M Shi Y Stein PD Wang Y 《Bioorganic & medicinal chemistry letters》2008,18(16):4696-4699
A series of acylguanidine derivatives were prepared and investigated as inhibitors of Factor Xa (FXa). These compounds were made by guanidine acylation with carboxylic acids using carbonyl diimidazole (CDI) as the coupling reagent. Conditions for the rapid synthesis and purification of these compounds are described along with their ability to inhibit FXa. The best FXa inhibitor is 1 with a FXa IC(50) of 6 nM. 相似文献
12.
Kowalchick JE Leiting B Pryor KD Marsilio F Wu JK He H Lyons KA Eiermann GJ Petrov A Scapin G Patel RA Thornberry NA Weber AE Kim D 《Bioorganic & medicinal chemistry letters》2007,17(21):5934-5939
Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated. 相似文献
13.
Masakazu Atobe Naomi Maekawara Masashi Kawanishi Hiroko Suzuki Eiichi Tanaka Shiro Miyoshi 《Bioorganic & medicinal chemistry letters》2013,23(7):2111-2116
A series of 1,1-dioxothieno[2,3-d]isothiazole (thienosultam) derivatives were designed and synthesized as novel ADAMTS-5 inhibitors for an investigation into a side chain of thienosultam for the S1′ pocket. The resulting compounds (19 and 24) show high ADAMTS-5 inhibition and other MMP selectivity, and these compounds show good oral bioavailability. 相似文献
14.
Song Y Clizbe L Bhakta C Teng W Wong P Huang B Tran K Sinha U Park G Reed A Scarborough RM Zhu BY 《Bioorganic & medicinal chemistry letters》2003,13(2):297-300
In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats. 相似文献
15.
Qiao JX Chang CH Cheney DL Morin PE Wang GZ King SR Wang TC Rendina AR Luettgen JM Knabb RM Wexler RR Lam PY 《Bioorganic & medicinal chemistry letters》2007,17(16):4419-4427
In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties. 相似文献
16.
In order to understand the structural basis of Factor Xa (FXa) specificity, structural complexes of FXa with its synthetic inhibitors are determined using a computational docking approach. The AutoDock suite of programs is used to determine the binding modes of the synthetic inhibitors such as 3- and 4-amidinobenzylphenyl ether (ABP), amidinophenyl pyruvic acid (APPA), diamidinobenzofuranyl ethene (DABE), and DX-9065a 2-(5'-amidino-2'-benzofuranyl)-3-(7'amidino-2'-napthyl)-propionic acid (ABAP) to FXa. The synthetic inhibitors docked in the present study are different in size, nature of linkage, and properties. Two sets of simulations were carried out for synthetic inhibitors docking to FXa. In the first set of simulations, no explicit water molecules were included. In the second set of simulations two explicit solvent molecules were considered. In all the computationally predicted synthetic inhibitor complexes of FXa, the specificity pocket residue Asp-189 is involved in hydrogen bonding with the bound inhibitor. The active site water molecule WAT522 is involved in hydrogen bonding with all the bound inhibitors. The computed energies clearly discriminate the high affinity from low affinity binders. 相似文献
17.
Tsutomu Nagata Toshiharu Yoshino Noriyasu Haginoya Kenji Yoshikawa Masatoshi Nagamochi Syozo Kobayashi Satoshi Komoriya Aki Yokomizo Ryo Muto Mitsuhiro Yamaguchi Ken Osanai Makoto Suzuki Hideyuki Kanno 《Bioorganic & medicinal chemistry》2009,17(3):1193-1206
In the early 1990’s, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity. 相似文献
18.
Zilun Hu Cailan Wang Wei Han Karen A. Rossi Jeffrey M. Bozarth Yiming Wu Steven Sheriff Joseph E. Myers Joseph M. Luettgen Dietmar A. Seiffert Ruth R. Wexler Mimi L. Quan 《Bioorganic & medicinal chemistry letters》2018,28(6):987-992
Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability. 相似文献
19.
Tanaka M Sagawa S Hoshi J Shimoma F Yasue K Ubukata M Ikemoto T Hase Y Takahashi M Sasase T Ueda N Matsushita M Inaba T 《Bioorganic & medicinal chemistry》2006,14(17):5781-5794
Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route. 相似文献
20.
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