Factor VIIa inhibitors: A prodrug strategy to improve oral bioavailability

Riggs, Jennifer R.; Kolesnikov, Aleksandr; Hendrix, John E.; Young, Wendy B.; Shrader, William D.; Vijaykumar, Dange; Stephens, Robin; Liu, Liang; Pan, Lin; Mordenti, Joyce; Green, Michael J.; Sukbuntherng, Juthamas

doi:10.1016/j.bmcl.2006.01.039

Cited by 28 publications

(19 citation statements)

References 15 publications

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“…Researchers at Celera Genomics attempted to improve oral bioavailability of compounds containing a biaryl P1 moiety, 5-amidinoindole. 37 A series of hydroxyl-, alkoxy-, and carbamate-amidine prodrugs were synthesized that showed moderate to good oral absorption of the prodrug in rat (typically 40% to 100%) but poor conversion to parent amidine, resulting in overall oral availability of Ͻ1% to 2% for the amidine drug. The authors noted that previous successes with amidine prodrugs were obtained with mono aryl structures (eg, benzamidine) or alkyl-amidines and hypothesized that the biaryl-amidine prodrugs were not recognized by the enzymatic machinery required for prodrug conversion.…”

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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Section: Shirk and Vlasukmentioning

confidence: 99%

Inhibitors of Factor VIIa/Tissue Factor

Shirk

Vlasuk

2007

ATVB

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“…Studies evaluating bleeding tendency [120] and surgical blood loss [121] have shown that inhibition earlier in the coagulation cascade, e.g., factor VIIa, may provide an increased These possible safety advantages lead Riggs et al [124] to focus on the development of an oral and selective factor VIIa inhibitor using a orodrug strategy.…”

Section: Iv12 Aromatic Amidoximes Prodrugs Of Amidines As Factor Vmentioning

confidence: 99%

Recent Developments in the Chemistry and in the Biological Applications of Amidoximes

Fylaktakidou¹,

Hadjipavlou‐Litina

Litinas³

et al. 2008

CPD

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Amidoximes are compounds bearing both a hydroxyimino and an amino group at the same carbon atom which makes them versatile building blocks for the synthesis of various heterocycles. Their importance in chemistry along with their rich biology, make amidoximes an attractive target for medicinal chemists, biochemists and biologists. Amidoximes and simple O-substituted derivatives possess very important biological activities functioning as antituberculotic, antibacterial, bacteriostatic, insecticidal, elminthicidal, antiviral, herbicidal, fungicidal, antineoplastic, antiarrythmic, antihypertensive, antihistaminic, anxiolytic-antidepressant, anti-inflammatory/antioxidant, antiaggregatory (NO donors) or plant growth regulatory agents. A number of amidoximes has already been used as drugs, or currently being in clinical trials. Their numerous pharmaceutical applications have been recently enriched, due to the fact that some mechanistic pathways, concerning their conversion to amidines, as well as their ability to release NO were clarified, giving a new insight to their mode of action and allowing the design of new therapeutic agents. The main subject of the present review paper is to highlight aspects concerning chemical and biological questions on this interesting class of compounds. Some new synthetic methodologies as well as improvements of previously reported general reactions involving amidoximes, acylated amidoximes, and amidines are presented. The biological applications of amidoximes over the end of 2006 are also extensively reviewed.

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“…1) display a wide range of pharmacological activities and therefore have been explored as a number of potential therapeutic agents [1] e.g. inhibitors of proteases involved in coagulation [2–3], antagonists of G-protein-coupled receptors [4–5], anti-angiogenic compounds [6] and inhibitors of endothelinconverting-enzyme [7]. 5-Alkyl substituted indoles e.g.…”

Section: Introductionmentioning

confidence: 99%