Design, synthesis, and SAR of monobenzamidines and aminoisoquinolines as factor Xa inhibitors

Zhang, Penglie; Zuckett, Jingmei F; Woolfrey, John; Tran, Katherine; Huang, Brian; Wong, Paul; Sinha, Uma; Park, Gary; Reed, Andrea; Malinowski, J; Hollenbach, Stan; Scarborough, Robert M.; Zhu, Bing‐Yan

doi:10.1016/s0960-894x(02)00234-2

Cited by 16 publications

(9 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…35). 127 The reversal of the amide bond as found in 199 (fXa IC 50 aminoisoquinoline found in 201 (fXa IC 50 5 646 nM). Unfortunately, the aminoisoquinoline moiety led to poor fXa potency.…”

Section: Group 5 Anthranilamides Disubstituted Benzenes and Diaminmentioning

confidence: 96%

See 1 more Smart Citation

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

View full text Add to dashboard Cite

Thromboembolic diseases are the leading causes of morbidity and mortality in the developed world. Anticoagulants provide effective treatment for venous or arterial thromboembolism. Two coagulation factors, factor Xa (fXa) and thrombin, are the primary targets under active investigation for anticoagulant therapy. fXa, in contrast to the multifunctional roles of thrombin in the coagulation cascade, converts prothrombin to thrombin collectively at the junction of the intrinsic and extrinsic pathway of coagulation. The effectiveness of fXa inhibitors as antithrombotic agents and their potentially reduced bleeding risks may offer superior therapeutic profiles with respect to thrombin inhibitors. After decades of research, many fXa inhibitors are now in the advanced stages of clinical trials. Unlike most reviews, which only provide incremental updates, this review provides an overview of fXa and the medicinal chemistry of its inhibitors. Overviews on coagulation models, antithrombotic therapy, and fXa will be provided, followed by the evolution of the medicinal chemistry of fXa inhibitors over the past few decades.

show abstract

Section: Group 5 Anthranilamides Disubstituted Benzenes and Diaminmentioning

confidence: 96%

“…17). 127 Based on 22, a series of N-amidinotetrahydroisoquinolines was prepared, as represented by the lead compound 43 (fXa IC 50 5 3,340 nM, fIIa IC 50 410 mM). 128 Further optimization led to 44 (fXa IC 50 5 56 nM, fIIa IC 50 410 mM).…”

Section: Synthetic Direct Fxa Inhibitorsmentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…7 ) with a 2'-sulfamoyl or 2'-methylsulfonyl substituted biphenyl group that are effective as factor Xa and factor VIIa inhibitors [44,45,46]. The substituted biphenyl structural element had already been used in the design of potent, selective factor Xa inhibitors [47,48,49,50]. Molecular modeling suggested that this biaryl part interacts with the distal pocket of the enzyme [48].…”

Section: Dual Inhibitors Of Factor Xa and Factor Viiamentioning

confidence: 99%

Dual Inhibitors of the Blood Coagulation Enzymes

Kranjc

Kikelj²

2004

CMC

View full text Add to dashboard Cite

The search for an ideal anticoagulant has spanned decades and has resulted in several approaches and the identification of novel target molecules for preventing and treating thrombosis. The first group of new anticoagulant agents acting through direct inhibition of coagulation factors were inhibitors of thrombin, but factor Xa inhibitors and, most recently, factor VIIa inhibitors have become attractive candidates. The structures of thrombin, factor Xa and factor VIIa show similarities in their active sites and, for this reason, attempts have been made to develop synthetic agents containing in a single molecule inhibitory activity against two of the enzymes of the blood coagulation cascade. Such dual inhibitors are now in preclinical studies and are, potentially, new anticoagulant drugs with improved properties. The emphasis of this review will be placed on dual inhibitors of thrombin/factor Xa and factor Xa/factor VIIa. Comparison of the active sites of these enzymes is included for better understanding of the structural demands to be met in designing effective dual inhibitors.

show abstract

“…7-Amidino-2-Naphthoanilide and 7-Amidino-2-Naphthalensulfonanilide Derivatives Hirayama et al 90 have recently published their efforts to discover FXa inhibitors, containing carboxamide and sulfonamide linkers. From their data, given in MR B is the most significant term followed be the indicator variable.…”

Section: Monobenzamidines and Amino-isoquinolinesmentioning

confidence: 99%

Current trends in quantitative structure activity relationships on FXa inhibitors: Evaluation and comparative analysis

Kontogiorgis¹,

Hadjipavlou‐Litina²

2004

Medicinal Research Reviews

View full text Add to dashboard Cite

This article evaluates the quantitative structure activity relationships of FXa inhibitors, using the C-QSAR program of Biobyte. Diaryloxypyridines, aminophenols, biaryl isoxazoline derivatives, 1,2-dibenzamidobenzenes, 3-amidinophenylalanine derivatives, benzoxazinones, naphthoanilides, tetrazoles, glucolic and mandelic acid derivatives were included in this survey. Clog P plays a significant role in the QSAR, especially as hydrophilicity. In the most of the cases, CMR/MR molar refractivity as well as sterimol parameters (B5 and L) are important. Electronic effects with the exception of the Hammett's constant sigmam, are not found to govern the biological activity. Es was found to be important indicator variables were used after the best model was found to account for the usual structural features.

show abstract

Design, synthesis, and SAR of monobenzamidines and aminoisoquinolines as factor Xa inhibitors

Cited by 16 publications

References 12 publications

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Dual Inhibitors of the Blood Coagulation Enzymes

Current trends in quantitative structure activity relationships on FXa inhibitors: Evaluation and comparative analysis

Contact Info

Product

Resources

About