Structure-based design and synthesis of pyrazinones containing novel P1 ‘side pocket’ moieties as inhibitors of TF/VIIa

Schweitzer, Barbara A.; Neumann, William L.; Rahman, Hayat; Kusturin, Carrie; Sample, Kirby R.; Poda, Gennadiy; Kurumbail, Ravi G.; Stevens, Anna M.; Stegeman, Roderick A.; Stallings, William C.; South, Michael S.

doi:10.1016/j.bmcl.2005.04.037

Cited by 17 publications

(7 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Key differences in the S2 pocket have been used to improve selectivity as well. FVIIa has a large S2 pocket with a unique Asp60 ( Figure 1A, yellow surface) that has been targeted by basic P2 moieties in FVIIa inhibitors, 14,22 whereas other coagulation proteases lack an acidic residue in that position. In contrast, the thrombin and FXa S2 pockets are markedly smaller, with the thrombin S2 pocket partially blocked by a rigid insertion loopTyr60AϪ Trp60D ( Figure 1B, yellow surface) and FXa S2 occluded by the side chain of Tyr99 ( Figure 2C, top green surface).…”

Section: State-of-the Artmentioning

confidence: 99%

“…A serine at position 190 in the S1 pocket is unique to FVIIa (versus Ala190 in thrombin and FXa), and some FVIIa inhibitors have been shown to form key hydrogen bonds with Ser190. 14,15 Interaction with the catalytic Ser195 via addition of a -amino group on the benzamidine contributes significantly to potency in a number of inhibitors. 8,16 In contrast, a series of compounds was shown to form a unique network of hydrogen bonds to Ser195 via a hydroxyl group on a non-P1 central ring.…”

Section: State-of-the Artmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitors of Factor VIIa/Tissue Factor

Shirk

Vlasuk

2007

ATVB

View full text Add to dashboard Cite

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...

show abstract

Section: State-of-the Artmentioning

confidence: 99%

Section: State-of-the Artmentioning

confidence: 99%

Inhibitors of Factor VIIa/Tissue Factor

Shirk

Vlasuk

2007

ATVB

View full text Add to dashboard Cite

show abstract

“…Some of the FVIIa inhibitors shown H-bond interactions with SER190 which shows significant interaction for anticoagulant activity. 21,22 The ribbon structure of FVIIa and active site residues after minimization of energy (MMFF force field used) is shown in Figure 2.…”

Section: Fviia Active Sitementioning

confidence: 99%

Factor VIIa and Factor IXa Inhibitors as Anticoagulants: A Review

Sahadeo¹,

Balkrishna²,

Suresh³

et al. 2017

IJPER

View full text Add to dashboard Cite

Introduction: Anticoagulants are used as preventive agents in deep vein thrombosis to prevent blood clots, venous and arterial thromboembolism, but the current therapy of anticoagulants have several limitations like patient variable response, enhanced chances of bleeding and heparin-induced thrombocytopenia (HIT). Factor VIIa and factor IXa play an important role in coagulation cascade and hence are promising targets for drug development. FIXa has been targeted by various means including oral inhibitors (TTP889), monoclonal antibodies (SB249417) and RNA aptamers which have passed various phases of clinical trials. Objectives: Though advances in development of inhibitors of FVIIa/TF and FIXa have reached various phases of clinical trials none of the clinical trial candidates have reached the market. Methodology: This review summarizes available information on FVIIa/TF and FIXa, their active site, crystallographic structure, available inhibitors, earlyphase clinical trial study and also the recent efforts in the discovery of FVIIa/TF and FIXa inhibitors. Summary: Despite the fact that more complexity is observed in designing of anticoagulant as FVIIa/TF complex and FIXa inhibitors, these will remain an important and validated target for the design and development of anticoagulants.

show abstract

“…11) [128]. This pocket also exists in thrombin, fXa and trypsin, however it contains Lys 192 , which is unique to fVIIa.…”

Section: Amidinophenyl-containing Pyrazinone Derivativesmentioning

confidence: 99%

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

Henry¹,

Desai²

2008

CHAMC

View full text Add to dashboard Cite

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...

show abstract

Structure-based design and synthesis of pyrazinones containing novel P1 ‘side pocket’ moieties as inhibitors of TF/VIIa

Cited by 17 publications

References 24 publications

Inhibitors of Factor VIIa/Tissue Factor

Inhibitors of Factor VIIa/Tissue Factor

Factor VIIa and Factor IXa Inhibitors as Anticoagulants: A Review

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

Contact Info

Product

Resources

About