5-Amidinobenzo[b]thiophenes as dual inhibitors of factors IXa and Xa

doi:10.1016/j.bmcl.2004.10.045

Bioorganic & Medicinal Chemistry Letters

Volume 15, Issue 1, 3 January 2005, Pages 29-35

https://doi.org/10.1016/j.bmcl.2004.10.045 Get rights and content

Abstract

Syntheses and SAR studies of 5-amidinobenzo[b]thiophene analogs provided compounds with low submicromolar factor IXa activity and equal or slightly better selectivity relative to factor Xa.

Graphical abstract

Syntheses and SAR studies of 5-amidinobenzo[b]thiophene analogs provided compounds with low submicromolar factor IXa potency and equal or slightly better selectivity relative to factor Xa.

Introduction

Thromboembolic diseases, such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and thromboembolic stroke, are the leading causes of morbidity and mortality in the developed countries. Conventional antithrombotic therapies using either heparin or warfarin have several limitations, including excessive bleeding, due to their targeting multiple factors within the coagulation cascade. To improve the benefit-to-risk ratio of antithrombotic drugs, small-molecule direct thrombin inhibitors and selective factor Xa (fXa) inhibitors are being extensively investigated.

The coagulation cascade is a proteolytic sequence of events, involving several serine proteases, leading to overall maintenance of hemostasis. The cascade consists of three systems: the intrinsic and extrinsic pathways that provide alternative routes for the generation of fXa, and a final common pathway that leads to thrombin formation. Factor IXa (fIXa) in the presence of cofactor fVIIIa and Ca²⁺ activates fX to fXa on the surface of platelets or endothelial cells via the intrinsic pathway.¹ FIXa seems to be essential for the amplification of coagulation, as indicated by the high bleeding tendency of hemophilia B patients (fIX deficiency). Inhibition of fIXa may provide ‘upstream’ inhibition of intrinsic coagulation and thrombus propagation, while leaving hemostasis intact via the fVIIa/tissue factor extrinsic pathway. It has been demonstrated that inhibition of fIXa either by active site-blocked fIXa or by fIX/fIXa antibody was effective in prevention of thrombus formation in animal models without increasing bleeding.²

These results suggested that potent and selective small-molecule fIXa inhibitors may have the potential to be viable therapeutic agents for the treatment of thromboembolic disorders with a reduced bleeding liability. Our initial goal was to identify a reversible, small-molecule, selective fIXa inhibitor as a tool molecule for animal studies.

High throughput screening of our proprietary fXa inhibitor collection identified amidinoindole 1.³ Compound 1 is a submicromolar lead for fIXa, however it is approximately 1000-fold more potent for fXa (fIXa K_i 0.66 μM, fXa K_i 0.00063 μM).⁴ In this paper, we describe the syntheses and structure activity relationships developed in an effort to optimize 1, which resulted in the 5-amidinobenzo[b]thiophene series 2 with both improved inhibitory activity for fIXa and improved selectivity relative to other relevant trypsin-like serine proteases.

Section snippets

Chemistry

Scheme 1 depicts the preparation of 5-amidinobenzo[b]-thiophene analog 3 and its homolog 4. Pd-catalyzed cyanation of methyl 5-cyano-3-benzothiophene acetate with zinc cyanide gave the methyl ester 5a.⁵ Alternately, a three-step sequence provided the ethyl ester 5b, namely, alkylation of 4-bromothiophenol with ethyl chloroacetoacetate followed by cyclization with polyphosphoric acid using a modified literature method,⁶ and then displacement of the bromide with copper cyanide. Alkylation of 5a

Results and discussion

The 5-amidinoindole group has been demonstrated, both computationally and experimentally, to have higher potency and selectivity for fXa compared with several other amidino bicyclic P1 groups not containing an N–H.¹⁰ This difference is presumably due to the ability to form the hydrogen bond between the indole NH and the oxygen atom of Ser195. In contrast, amidinoindole 1 showed weaker fIXa potency compared with fXa potency. This may be due to one or both of the following two possibilities.

Conclusion

We identified a series of 5-amidinobenzo[b]thiophenes as low submicromolar fIXa inhibitors, some of which showed improved selectivity over fXa. The most selective compounds prepared herein were 6- to 10-fold more selective for fIXa relative to fXa (26 and 29-R); however, they were less potent (fIXa K_i 0.4–0.8 μM) than the compounds containing the benzimidazole phenylamide P4 group. Further varying the P4 substituents did not result in compounds with improved fIXa potency and selectivity. In

Acknowledgements

We would like to thank Dr. Leslie Robinson and Dr. Jinglan Zhou for their assistance in computational library design and automated synthesis. We would also like to thank Dr. Joanne Smallheer and Dr. Douglas Batt for their suggestions on the manuscript.

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5-Amidinobenzo[b]thiophenes as dual inhibitors of factors IXa and Xa

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Results and discussion

Conclusion

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Clin. Invest.

Thromb. Haemostasis

Arterioscl. Throm. Vas.

Thromb. Haemostasis

J. Thorac. Cardiovasc. Surg.

Thromb. Haemostatsis

Synth. Commun.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Tetrahedron Lett.