Selective and orally bioavailable phenylglycine tissue factor/factor VIIa inhibitors

Zbinden, Katrin Groebke; Obst‐Sander, Ulrike; Hilpert, Kurt; Kühne, Holger; Banner, David W.; Böhm, Hans‐Joachim; Ståhl, Martin; Ackermann, Jean; Alig, Leo; Weber, Lutz; Wessel, Hans Peter; Riederer, Markus A.; Tschopp, Thomas B.; Lavé, Thierry

doi:10.1016/j.bmcl.2005.04.079

Cited by 33 publications

(13 citation statements)

References 42 publications

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“…However, this was attributed to the unusual nature of the inhibitor, in which the amidino NH groups of the inhibitor induced ∼180 degree rotation of the c192-c193 peptide bond such that the interactions between the NH groups of the inhibitor could occur with the c192 main chain C=O group (100), Thus, a normal conformation of the c192-c193 peptide bond would be changed to the unexpected nonstandard one. Flipped peptide bond between Lys-c192 and Gly-c193 of FVIIa has also been observed by Olivero et al (101) and by Zbinden et al (102). In these structures, nitrogen at the para position of benzamidine moiety of the sulfonamide inhibitor (101) or the phenylglycine amide inhibitor (102) makes hydrogen bond with the main chain carbonyl group of Gly-c192 and the hydroxyl group of Ser-c195.…”

Section: 8 Incompletely Formed Oxyanion Hole In Fviia/stf and Its supporting

confidence: 60%

Structural biology of factor VIIa/tissue factor initiated coagulation

Vadivel¹

2012

Front Biosci

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Factor VII (FVII) consists of an N-terminal gamma-carboxyglutamic acid domain followed by two epidermal growth factor-like (EGF1 and EGF2) domains and the C-terminal protease domain. Activation of FVII results in a two-chain FVIIa molecule consisting of a light chain (Gla-EGF1-EGF2 domains) and a heavy chain (protease domain) held together by a single disulfide bond. During coagulation, the complex of tissue factor (TF, a transmembrane glycoprotein) and FVIIa activates factor IX (FIX) and factor X (FX). FVIIa is structurally “zymogen-like” and when bound to TF, it is more “active enzyme-like.” FIX and FX share structural homology with FVII. Three structural biology aspects of FVIIa/TF are presented in this review. One, regions in soluble TF (sTF) that interact with FVIIa as well as mapping of Ca2+, Mg2+, Na+ and Zn2+ sites in FVIIa and their functions; two, modeled interactive regions of Gla and EGF1 domains of FXa and FIXa with FVIIa/sTF; and three, incompletely formed oxyanion hole in FVIIa/sTF and its induction by substrate/inhibitor. Finally, an overview of the recognition elements in TF pathway inhibitor is provided.

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Section: 8 Incompletely Formed Oxyanion Hole In Fviia/stf and Its supporting

confidence: 60%

Structural biology of factor VIIa/tissue factor initiated coagulation

Vadivel¹

2012

Front Biosci

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“…16,18 -22 Some FVIIa inhibitors have been shown to induce a flipped conformation of the amide bond between Lys192 and Gly193 which results in an enzymatically incompetent oxyanion hole. 8,19,20 The 180°rotation of the Lys192-Gly193 bond is stabilized by a hydrogen bond with Gln143, but other tyrpsin-like proteases do not appear to have a suitable partner in that location for hydrogen bond formation, which may explain the observed selectivity for FVIIa. Key differences in the S2 pocket have been used to improve selectivity as well.…”

Section: State-of-the Artmentioning

confidence: 95%

“…In the first report, Zbinden et al demonstrated that masking the P1 benzamidine moiety as an amidoxime prodrug increased the oral bioavailability of the active drug from 2% to 30% in the rat, and a double prodrug containing both the amidoxime modification and an ester modification of an acidic group ("22", Figure 2) resulted in a surprising 100% oral bioavailability. 19 However, the active parent inhibitor had only moderate in vitro potency (K i ϭ190 nmol/L) and poor activity in plasma as measured in the PT clotting assay; no in vivo activity was reported. In a subsequent report, Zbinden et al demonstrated antithrombotic activity after oral administration of a double amidoxime/ester prodrug of another FVIIa/TF inhibitor with improved potency (81 nmol/L) and markedly better activity in plasma.…”

Section: Shirk and Vlasukmentioning

confidence: 99%

Inhibitors of Factor VIIa/Tissue Factor

Shirk

Vlasuk

2007

ATVB

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Abstract-The formation of the proteolytic complex composed of the serine protease Factor VIIa and the cell-associated glycoprotein tissue factor (FVIIa/TF) initiates a cascade of amplified zymogen activation reactions leading to thrombus formation. The critical role of the coagulation cascade in pathological thrombosis has been the basis for significant efforts to design selective inhibitors of the protease components as new anticoagulant alternatives for the treatment of thrombotic diseases. However, for the new generation of anticoagulant drugs in development that primarily target protease complexes distal from FVIIa/TF, the differential between efficacy and safety as defined by bleeding is unresolved. Targeting the FVIIa/TF complex has several theoretical advantages that exploit the amplified nature of the coagulation cascade. However, progress on the development of clinical-stage FVIIa/TF-based anticoagulants has not been as successful to date. This review summarizes recent efforts in the discovery of synthetic inhibitors of FVIIa/TF. Key Words: anticoagulants Ⅲ factor VIIa (FVIIa) Ⅲ tissue factor Ⅲ serine protease inhibitors Ⅲ coagulation H emostasis is achieved through a highly regulated and coordinated interplay of protein and cellular components designed to respond quickly to vascular insult. Critical in this rapid response is the initiation of blood coagulation by a proteolytic complex composed of the serine protease factor VIIa (FVIIa) and its cell-associated cofactor tissue factor (TF). Tissue factor is a transmembrane glycoprotein that is normally found in subendothelial structures throughout the vasculature. Exposure of TF to blood, through physical damage to the lining of the blood vessel or increased expression in endothelial and monocytic cells in response to certain inflammatory signals, permits an interaction with FVIIa, which is present at trace levels in the circulation. The formation of the FVIIa/TF complex is the critical step that initiates the sequentially amplified cascade of proteolytic activation steps that ultimately leads to the generation of the protease thrombin and thrombus formation. 1 The critical nature of the FVIIa/TF complex in the process of blood coagulation makes it an attractive candidate for the development of antithrombotic agents that can inhibit complex formation or catalytic activity. An antithrombotic agent based on the inhibition of FVIIa/TF may have theoretical advantages over the inhibition of downstream coagulation proteases such as factor Xa (FXa) or thrombin based on the several thousand-fold amplification that occurs after initiation by FVIIa/TF. The success of several small protein-and antibody-based inhibitors of the FVIIa/TF pathway in preclinical models and clinical trials 1,2 has led to substantial interest in the development of orally active small molecule inhibitors of the enzyme active site that could be used for the long-term prevention or treatment of thrombosis. Vitamin K antagonists such as warfarin, which have been used clinically for more than 5...

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“…A group of phenylglycine derivatives have been reported by Zbinden and co-workers that show promising oral bioavailability when used in the double pro-drug form [119,120]. Among the sev- Fig.…”

Section: Amidinophenyl Derivatized Phenylglycinesmentioning

confidence: 99%

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

Henry¹,

Desai²

2008

CHAMC

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Physiologic clotting is a defensive action. The new cell-based model of hemostasis proposes three steps -initiation, amplification and propagation -occurring on specific cell surfaces to generate a thrombus in a tightly regulated manner. The initiation phase relies on key players including tissue factor (TF), factor VIIa (fVIIa), platelets, Ca 2+ , phospholipids, and factor X/Xa (fX/fXa). Exposure of TF on sub-endothelial and other blood cells triggers a coagulation response, which may have to be inhibited to prevent a deleterious thrombotic effect. Inhibiting TF-initiated coagulation, akin to 'nipping coagulation in the bud', is predicted to have major advantages, including a more efficient separation of the antithrombotic and hemorrhagic responses. The availability of crystal structures of TF, fVIIa and TFfVIIa complex makes structure-based drug design feasible. Although no initiation phase small molecule inhibitor has reached the clinic as yet, several molecules have displayed promise. We discuss recent results on the discovery of inhibitors of the initiation phase with special emphasis on peptides, peptidomimetics and organic small molecules.Key Words: Anticoagulants, coagulation, factor VIIa, tissue factor, thrombin, factor Xa, Enzyme Inhibition, small molecule inhibitors. CELL-BASED HEMOSTASISPhysiologic clotting is a defensive action preventing excessive loss of blood and infiltration of microbes. The physiologic mechanism that produces this defensive reaction is an enzymatic cascade ( Fig. 1), proposed nearly 50 years ago [1,2]. In vivo, the enzymatic reactions occur on specific cell surfaces. The cell-dependent coagulation cascade is proposed to proceed sequentially in three stepsinitiation, amplification and propagation -on specific cell surfaces to generate a thrombus in a tightly regulated manner [3][4][5]. InitiationTissue factor (TF) is an integral membrane protein present on several extravascular cells [6] and is the most important initiator of coagulation. Under normal conditions, it is sequestered from circulating proteinases, especially factor VII (fVII), thus preventing inappropriate initiation of clotting. Vascular injury exposes TF to blood, resulting in rapid complex formation with free activated fVII (fVIIa) on TF-bearing cells (Fig. 1). It is believed that some fVIIa is always present in blood (~1-2%), which can rapidly interact with TF to initiate clotting. The formation of TF/fVIIa complex activates the circulating factor X (fX) to fXa, the formation of which can induce further production of fVIIa and fXa [7][8][9]. The TF/fVIIa complex can also activate factor IX (fIX) to fIXa [10][11][12], which in turn can result in more fXa. The earliest fXa formed remains localized to the site of TF-bearing cells, yet is free enough to form the prothrombinase complex with factor Va (fVa). The small amount of the prothrombinase complex so formed is responsible for the initial production of thrombin from prothrombin [12]. The in vivo source of the initial fVa needed for the assembly of p...

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Selective and orally bioavailable phenylglycine tissue factor/factor VIIa inhibitors

Cited by 33 publications

References 42 publications

Structural biology of factor VIIa/tissue factor initiated coagulation

Structural biology of factor VIIa/tissue factor initiated coagulation

Inhibitors of Factor VIIa/Tissue Factor

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

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