Potent 4-amino-5-azaindole factor VIIa inhibitors

Hu, Huiyong; Kolesnikov, Aleksandr; Riggs, Jennifer R.; Wesson, Kieron E.; Stephens, Robin; Leahy, Ellen M.; Shrader, William D.; Sprengeler, Paul A.; Green, Michael J.; Sanford, Ellen; Nguyen, Margaret; Gjerstad, Erik; Cabuslay, Ronnel; Young, Wendy B.

doi:10.1016/j.bmcl.2006.06.016

Cited by 32 publications

(22 citation statements)

References 14 publications

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“…The 5-aminopyrrolo-pyridine and 5-azaindole P1 scaffolds described in these reports are markedly less basic, with a calculated pKa of Ϸ8.8 and Ϸ7.8, respectively, versus pKa Ϸ11 to 12 for benzamidine. 32,33 However, it is not clear whether these modifications are sufficient to significantly improve oral bioavailability, as no pharmacokinetic data are reported. Researchers at Astellas Pharma Inc took a different approach, replacing the amidine on the P1 benzene ring of a 90 nmol/L FVIIa/TF inhibitor with "neutral" 3-aminocarbonyl or 4-aminomethyl groups.…”

Section: Shirk and Vlasukmentioning

confidence: 99%

“…Researchers at Celera Genomics began with potent FVIIa/TF inhibitors that contained biaryl amidine P1 moieties, such as 5-amidinoindole and 5-amidinobenzimidazole, and replaced these scaffolds with less basic heterocyclic scaffolds that could potentially interact with key residues in the S1 pocket. 24,32,33 These inhibitors lose substantial potency initially but typically gained significant selectivity against thrombin, FXa, and trypsin, even before further modification. By further optimizing the inhibitor to interact with the S1Ј pocket or the loop separating the S2 and S1Ј pockets, a highly potent (20 nmol/L K i ) and selective inhibitor with a 5-aminopyrrolo-pyridine P1 scaffold was generated (compound "10", Figure 2).…”

Section: Shirk and Vlasukmentioning

confidence: 99%

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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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Section: Shirk and Vlasukmentioning

confidence: 99%

Section: Shirk and Vlasukmentioning

confidence: 99%

Inhibitors of Factor VIIa/Tissue Factor

Shirk

Vlasuk

2007

ATVB

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“…The 5-azaindole moiety is likely to be partially protonated at pH 7.4 (calculated pK A ~7.9) resulting in good recognition of Asp 189 and concomitantly high binding affinity. Introducing 4-amino substitution on the 5-azaindole ring was thought to enhance the proportion of protonated species (calculated pK A ~9.9), thus resulting in even better recognition [146]. In fact, inhibitor Ai3 containing the carboxylate group, which most probably binds to Lys 192 , and the difluorophenylurea group, which probably engages Lys 60A and His 57 , displayed a K I of 2.6 nM against TF-fVIIa, while displaying nearly 10,000-fold poor affinity for thrombin, fXa and trypsin.…”

Section: Aza-indolesmentioning

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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“…The structural considerations of the designed molecules were further supported by the docking study with target enzyme, L-glutamine: D-fructose-6-phosphate amidotransferase (EC 2.6.1. 16), known under the trivial name of glucosamine-6-phosphatesynthase (GlcN-6-P synthase), as such new target for antimicrobial studies [22]. We report herein, synthesis, X-ray crystal structure analysis, molecular docking and antimicrobial evaluation of new pyrrolo [3,2-c]pyridine derivatives.…”

Section: Introductionmentioning

confidence: 98%

“…Other examples include the synthetic pyrrolopyridine derivative diazarebeccamycin 2 is a potent anticancer agent [2], pyrrolo [2,3-c]pyridine 3 which has demonstrated activity as an inhibitor of HIV-1 attachment to CD4 + T cells [3] and pyrrolo [2,3-b]pyridine 4 is a potent p38 kinase inhibitor [4]. Pyrrolopyridines also posses significant biological applications such as antimicrobial [5][6][7][8][9], analgesic [10], antimalarial [11], antiproliferative [12], antihypertensive [13], cannabinoid activity [14,15] and Factor VIIa inhibitors [16]. As a result of our considerable interest in the synthesis of pyridine-containing compounds and their antimicrobial activity [17], we initiated a programme directed towards the synthesis of new pyrrolopyridine compounds.…”

Section: Introductionmentioning

confidence: 99%