Structure and property based design of factor Xa inhibitors: Pyrrolidin-2-ones with biaryl P4 motifs

Young, Robert J.; Borthwick, Alan D.; Brown, David F.M.; Burns-Kurtis, Cynthia L.; Campbell, Matthew; Chan, Carmel T.; Charbaut, Marie; Chung, Chun‐wa; Convery, M.A.; Kelly, Henry A.; King, N. Paul; Kleanthous, Savvas; Mason, Andrew M.; Pateman, Anthony J.; Patikis, Angela; Pinto, Ivan L.; Pollard, Derek; Senger, Stefan; Shah, Gita P.; Toomey, John R.; Watson, Nigel S.; Weston, Helen E.

doi:10.1016/j.bmcl.2007.11.023

Cited by 25 publications

(23 citation statements)

References 16 publications

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“…A large number of scaffolds have been studied for direct inhibition of FXa including the aminopiperidines [25], piperazines [26], diaminocycloalkanes [27], lactams [28,29], oxazolidinones [30], amino acids (e.g., glycine, proline, and β-aminoproionate) [31,32], anthranilamides [33], isoxazoles [34], pyrazoles [24,35], indazoles [36], indoles [37,38], and dihydropyrazolopyridinones [23,39]. The overall philosophy in the design of these scaffolds is to have a three-component system, which includes a core scaffold and two hydrophobic arms that provide a non-linear geometry considered important for FXa recognition.…”

Section: Introductionmentioning

confidence: 99%

Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold

Al‐Horani

Mehta

Desai

2012

European Journal of Medicinal Chemistry

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Direct inhibition of coagulation factor Xa (FXa) carries significant promise for developing effective and safe anticoagulants. Although a large number of FXa inhibitors have been studied, each can be classified as either possessing a highly flexible or a rigid core scaffold. We reasoned that an intermediate level of flexibility will provide high selectivity for FXa considering that its active site is less constrained in comparison to thrombin and more constrained as compared to trypsin. We studied several core scaffolds including 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid for direct FXa inhibition. Using a genetic algorithm-based docking and scoring approach, a promising candidate 23 was identified, synthesized, and found to inhibit FXa with a Ki of 28 μM. Optimization of derivative 23 resulted in the design of a potent dicarboxamide 47, which displayed a Ki of 135 nM. Dicarboxamide 47 displayed at least 1852-fold selectivity for FXa inhibition over other coagulation enzymes and doubled PT and aPTT of human plasma at 17.1 μM and 20.2 μM, respectively, which are comparable to those of clinically relevant agents. Dicarboxamide 47 is expected to serve as an excellent lead for further anticoagulant discovery.

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Section: Introductionmentioning

confidence: 99%

Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold

Al‐Horani

Mehta

Desai

2012

European Journal of Medicinal Chemistry

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“…168 Optimization of P4 in the pyrrolidinone series using biaryl motifs yielded a new series of analogues, as illustrated by 110 (fXa K i 5 0.2 nM, EC 1.5 Â PT 5 21.3 mM) and 111 (fXa K i o0.3 nM, EC 1.5 Â PT 5 38.9 mM). 169 Compound 111 showed oral bioavailability of 29%, a clearance of 20 mL/min/kg, and a half-life of 0.6 hr in Sprague-Dawley rats. Although the series showed oral bioavailability in rats, the in vitro anticoagulant activity (EC 1.5 Â PT ) was suboptimal.…”

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confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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Thromboembolic diseases are the leading causes of morbidity and mortality in the developed world. Anticoagulants provide effective treatment for venous or arterial thromboembolism. Two coagulation factors, factor Xa (fXa) and thrombin, are the primary targets under active investigation for anticoagulant therapy. fXa, in contrast to the multifunctional roles of thrombin in the coagulation cascade, converts prothrombin to thrombin collectively at the junction of the intrinsic and extrinsic pathway of coagulation. The effectiveness of fXa inhibitors as antithrombotic agents and their potentially reduced bleeding risks may offer superior therapeutic profiles with respect to thrombin inhibitors. After decades of research, many fXa inhibitors are now in the advanced stages of clinical trials. Unlike most reviews, which only provide incremental updates, this review provides an overview of fXa and the medicinal chemistry of its inhibitors. Overviews on coagulation models, antithrombotic therapy, and fXa will be provided, followed by the evolution of the medicinal chemistry of fXa inhibitors over the past few decades.

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“…In our previous work [17,18], derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one (PQ, 1) were found to be perspective FXa inhibitors, with IC50 values in the range of 0.7 to 40 μM. These identified inhibitors represent hybrid molecules consisting of dihydroquinoline (2) [18], pyrrolidinone (3) [19], and rhodanine (4) [20] (see Figure 3), which are known to be active moieties of different inhibitors of coagulation factors. (1) and structural fragments of some known inhibitors of coagulation factors: 1,2-dihydroquinoline (2), pyrrolidinone (3), and rhodanine (4).…”

Section: Design Of Pyrrolo[3 21-ij]quinolin-2(1h)-one-based Derivativesmentioning

confidence: 99%

Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

et al. 2020

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Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC50 value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.

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Structure and property based design of factor Xa inhibitors: Pyrrolidin-2-ones with biaryl P4 motifs

Cited by 25 publications

References 16 publications

Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold

Potent direct inhibitors of factor Xa based on the tetrahydroisoquinoline scaffold

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

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