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Title: Synthesis and P1′ SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors

Authors:
 [1]; ; ; ; ; ; ; ; ; ; ; ; ; ORCiD logo
  1. (Uladzimir)
Publication Date:
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1396355
Grant/Contract Number:
AC02-06CH11357
Resource Type:
Journal Article: Publisher's Accepted Manuscript
Journal Name:
Bioorganic and Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 26; Journal Issue: 20; Related Information: CHORUS Timestamp: 2017-10-04 16:41:16; Journal ID: ISSN 0960-894X
Publisher:
Elsevier
Country of Publication:
United Kingdom
Language:
English

Citation Formats

Ladziata, Vladimir, Glunz, Peter W., Zou, Yan, Zhang, Xiaojun, Jiang, Wen, Jacutin-Porte, Swanee, Cheney, Daniel L., Wei, Anzhi, Luettgen, Joseph M., Harper, Timothy M., Wong, Pancras C., Seiffert, Dietmar, Wexler, Ruth R., and Priestley, E. Scott. Synthesis and P1′ SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors. United Kingdom: N. p., 2016. Web. doi:10.1016/j.bmcl.2016.08.088.
Ladziata, Vladimir, Glunz, Peter W., Zou, Yan, Zhang, Xiaojun, Jiang, Wen, Jacutin-Porte, Swanee, Cheney, Daniel L., Wei, Anzhi, Luettgen, Joseph M., Harper, Timothy M., Wong, Pancras C., Seiffert, Dietmar, Wexler, Ruth R., & Priestley, E. Scott. Synthesis and P1′ SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors. United Kingdom. doi:10.1016/j.bmcl.2016.08.088.
Ladziata, Vladimir, Glunz, Peter W., Zou, Yan, Zhang, Xiaojun, Jiang, Wen, Jacutin-Porte, Swanee, Cheney, Daniel L., Wei, Anzhi, Luettgen, Joseph M., Harper, Timothy M., Wong, Pancras C., Seiffert, Dietmar, Wexler, Ruth R., and Priestley, E. Scott. 2016. "Synthesis and P1′ SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors". United Kingdom. doi:10.1016/j.bmcl.2016.08.088.
@article{osti_1396355,
title = {Synthesis and P1′ SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors},
author = {Ladziata, Vladimir and Glunz, Peter W. and Zou, Yan and Zhang, Xiaojun and Jiang, Wen and Jacutin-Porte, Swanee and Cheney, Daniel L. and Wei, Anzhi and Luettgen, Joseph M. and Harper, Timothy M. and Wong, Pancras C. and Seiffert, Dietmar and Wexler, Ruth R. and Priestley, E. Scott},
abstractNote = {},
doi = {10.1016/j.bmcl.2016.08.088},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 20,
volume = 26,
place = {United Kingdom},
year = 2016,
month =
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.bmcl.2016.08.088

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  • Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.
  • Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.
  • The virally encoded NS3 protease is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The design and synthesis of 15-membered ring {beta}-strand mimics which are capable of inhibiting the interactions between the HCV NS3 protease enzyme and its polyprotein substrate will be described. The binding interactions between a macrocyclic ligand and the enzyme were explored by NMR and molecular dynamics, and a model of the ligand/enzyme complex was developed.