Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa–Tissue Factor Complex

Zhang, Xiaojun; Glunz, Peter W.; Johnson, James A.; Jiang, Wen; Jacutin-Porte, Swanee; Ladziata, Vladimir; Yan, Zaoxue; Phillips, Monique; Wurtz, Nicholas R.; Parkhurst, Brandon L.; Harper, Timothy M.; Cheney, Daniel L.; Luettgen, Joseph M.; Wong, Pancras C.; Seiffert, Dietmar; Wexler, Ruth R.; Priestley, E. Scott

doi:10.1021/acs.jmedchem.6b00469

Cited by 15 publications

(13 citation statements)

References 33 publications

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“…Of note, the treatment of phosphonate with nucleophilic basic reagents like NaOH [ 144 ], LiOH [ 145 ] or NaHCO 3 [ 146 ] is not suitable to produce phosphonic acid. Indeed, these conditions yield phosphonic acid mono-esters.…”

Section: Reviewmentioning

confidence: 99%

Phosphonic acid: preparation and applications

Sevrain¹,

Berchel²,

Couthon³

et al. 2017

Beilstein J. Org. Chem.

132

103

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The phosphonic acid functional group, which is characterized by a phosphorus atom bonded to three oxygen atoms (two hydroxy groups and one P=O double bond) and one carbon atom, is employed for many applications due to its structural analogy with the phosphate moiety or to its coordination or supramolecular properties. Phosphonic acids were used for their bioactive properties (drug, pro-drug), for bone targeting, for the design of supramolecular or hybrid materials, for the functionalization of surfaces, for analytical purposes, for medical imaging or as phosphoantigen. These applications are covering a large panel of research fields including chemistry, biology and physics thus making the synthesis of phosphonic acids a determinant question for numerous research projects. This review gives, first, an overview of the different fields of application of phosphonic acids that are illustrated with studies mainly selected over the last 20 years. Further, this review reports the different methods that can be used for the synthesis of phosphonic acids from dialkyl or diaryl phosphonate, from dichlorophosphine or dichlorophosphine oxide, from phosphonodiamide, or by oxidation of phosphinic acid. Direct methods that make use of phosphorous acid (H3PO3) and that produce a phosphonic acid functional group simultaneously to the formation of the P–C bond, are also surveyed. Among all these methods, the dealkylation of dialkyl phosphonates under either acidic conditions (HCl) or using the McKenna procedure (a two-step reaction that makes use of bromotrimethylsilane followed by methanolysis) constitute the best methods to prepare phosphonic acids.

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Section: Reviewmentioning

confidence: 99%

Phosphonic acid: preparation and applications

Sevrain¹,

Berchel²,

Couthon³

et al. 2017

Beilstein J. Org. Chem.

132

103

View full text Add to dashboard Cite

show abstract

“…There are also examples when trifluoroacetic acid (TFA) [ 17 , 33 , 34 ] or HClO 4 [ 35 , 36 ] was used to catalyze the hydrolyses. Sodium hydroxide is the most commonly used reagent in alkaline hydrolysis [ 37 , 38 , 39 , 40 , 41 ], but there are also examples of the application of KOH [ 42 ], LiOH [ 40 , 43 ] and NaHCO 3 [ 44 ]. The alkaline hydrolysis is irreversible and less corrosive, but alkali-sensitive molecules can be damaged.…”

Section: Introductionmentioning

confidence: 99%

The Hydrolysis of Phosphinates and Phosphonates: A Review

Harsági

Keglevich

2021

Molecules

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Phosphinic and phosphonic acids are useful intermediates and biologically active compounds which may be prepared from their esters, phosphinates and phosphonates, respectively, by hydrolysis or dealkylation. The hydrolysis may take place both under acidic and basic conditions, but the C-O bond may also be cleaved by trimethylsilyl halides. The hydrolysis of P-esters is a challenging task because, in most cases, the optimized reaction conditions have not yet been explored. Despite the importance of the hydrolysis of P-esters, this field has not yet been fully surveyed. In order to fill this gap, examples of acidic and alkaline hydrolysis, as well as the dealkylation of phosphinates and phosphonates, are summarized in this review.

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“…Successful examples of approved macrocyclic peptidomimetic drugs are numerous inhibitors of the NS3/4A serine protease of the hepatitis C virus, such as simeprevir, paritaprevir, grazoprevir, voxilaprevir, and glecaprevir, which are derived from the linear analogues boceprevir, telaprevir, and asunaprevir. Many other examples of potent and selective experimental macrocyclic serine protease inhibitors have been described, including inhibitors of the clotting enzymes thrombin, factor VIIa or factor XIa, and of the fibrinolytic protease plasmin . These reports encouraged us to test various macrocyclizations for the design of new furin inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin

et al. 2019

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The activation of viral glycoproteins by the host protease furin is an essential step in the replication of numerous pathogenic viruses. Thus, effective inhibitors of furin could serve as broad‐spectrum antiviral drugs. A crystal structure of an inhibitory hexapeptide derivative in complex with furin served as template for the rational design of various types of new cyclic inhibitors. Most of the prepared derivatives are relatively potent furin inhibitors with inhibition constants in the low nanomolar or even sub‐nanomolar range. For seven derivatives the crystal structures in complex with furin could be determined. In three complexes, electron density was found for the entire inhibitor. In the other cases the structures could be determined only for the P6/P5‐P1 segments, which directly interact with furin. The cyclic derivatives together with two non‐cyclic reference compounds were tested as inhibitors of the proteolytic activation and replication of respiratory syncytial virus in cells. Significant antiviral activity was found for both linear reference inhibitors, whereas a negligible efficacy was determined for the cyclic derivatives.

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Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa–Tissue Factor Complex

Cited by 15 publications

References 33 publications

Phosphonic acid: preparation and applications

Phosphonic acid: preparation and applications

The Hydrolysis of Phosphinates and Phosphonates: A Review

Design, Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin

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