Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P1 structure–activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides

Jia, Zhaozhong J.; Wu, Yanhong; Huang, Wenrong; Goldman, Erick A.; Zhang, Penglie; Woolfrey, John; Wong, Paul; Huang, Brian; Sinha, Uma; Park, Gary; Reed, Andrea; Scarborough, Robert M.; Zhu, Bing‐Yan

doi:10.1016/s0960-894x(02)00239-1

Cited by 21 publications

(9 citation statements)

References 11 publications

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“…RPR208944 (55) from Aventis bearing the 5-and 6-chlorobenzothiophene moieties have been reported. Millennium has described 2-naphthyl derivatives such as 57 or 58 [31][32][33], however, with basic residues in the P4 site.…”

Section: Synopsis On Non-basic P1 Groupsmentioning

confidence: 99%

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)

Straub¹,

Roehrig²,

Hillisch³

2010

CTMC

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Several clinical candidates have now emerged as a result of an intense search for orally available, antithrombotic factor Xa inhibitors. This review highlights the discovery of XareltoTM (Rivaroxaban) starting from an initial tetrahydrophthalimide screening hit. The major breakthrough was the finding that a chlorothiophene moiety can undergo an interaction in the S1 binding site thus leading to high potency combined with favorable oral bioavailability. The binding mode of this P1 moiety is discussed, and further non-basic S1 binders of this new type are reviewed.

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Section: Synopsis On Non-basic P1 Groupsmentioning

confidence: 99%

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)

Straub¹,

Roehrig²,

Hillisch³

2010

CTMC

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“…8 Although SN429 ( 16 ) is a very potent factor Xa inhibitor in vitro , the compound has poor bioavailability ( F ϭ 4%) in dogs with a short in vivo half-life. For example, a series of 1-(2-naphthyl)-1 H -pyrazole-5-carboxylamides was developed as factor Xa inhibitors based on the structure of SN429 ( 16 ).…”

Section: P K Amentioning

confidence: 99%

Strategies for Enhancing Oral Bioavailability and Brain Penetration

Shook¹,

Jackson²

2008

The Practice of Medicinal Chemistry

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“…In their earlier patents [71][72][73][74], they reported compounds with a 2'-sulfamoyl or 2'-methylsulfonyl substituted biphenyl group, which had already been used in the design of potent, selective factor Xa inhibitors [75][76][77][78]. Compounds 46-50 (Fig.…”

Section: Phenyl Derivativesmentioning

confidence: 99%

Recent Advances in the Discovery of Tissue Factor/Factor VIIa Inhibitors and Dual Inhibitors of Factor VIIa/Factor Xa

Kranjc¹,

Kikelj²,

Mašič

2005

CPD

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The search for an ideal anticoagulant has spanned decades and has taken several approaches to the identification of novel target molecules for preventing and treating thrombosis. In the group of anticoagulants acting through direct inhibition of coagulation factors, most research has focused on thrombin and factor Xa inhibitors. Attention has been drawn most recently to factor VIIa as a promising anticoagulation target, because of its role in complex with tissue factor, in initiating the coagulation cascade following blood vessel damage. Several reports suggest that inhibitors of the tissue factor/factor VIIa complex prevent thrombosis with a lower bleeding risk than other types of inhibitors. Accordingly, there is increasing interest in the generation of potent and selective small-molecule factor VIIa inhibitors that can be safely administered once or twice daily in an oral formulation with no need for routine coagulation monitoring. The emphasis of this review will be placed on recent advances in the development of the small-molecule inhibitors of factor VIIa complexed with tissue factor. The role of factor VIIa and tissue factor as initiators of the coagulation cascade following blood vessel damage is described, along with the structure of the active site of factor VIIa.

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Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P1 structure–activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides

Cited by 21 publications

References 11 publications

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)

Strategies for Enhancing Oral Bioavailability and Brain Penetration

Recent Advances in the Discovery of Tissue Factor/Factor VIIa Inhibitors and Dual Inhibitors of Factor VIIa/Factor Xa

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Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P1 structure–activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides

Cited by 21 publications

References 11 publications

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto&#8482; (Rivaroxaban)

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto&#8482; (Rivaroxaban)

Strategies for Enhancing Oral Bioavailability and Brain Penetration

Recent Advances in the Discovery of Tissue Factor/Factor VIIa Inhibitors and Dual Inhibitors of Factor VIIa/Factor Xa

Contact Info

Product

Resources

About

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)

Entering the Era of Non-Basic P1 Site Groups: Discovery of Xarelto™ (Rivaroxaban)