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Title: Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles

Abstract

The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It has been a target of choice for intensive drug discovery research. On the basis of an active pentapeptide inhibitor, 1, we envisioned that macrocyclization from the P2 proline to P3 capping could enhance binding to the backbone Ala156 residue and the S4 pocket. Thus, a number of P2 proline-based macrocyclic {alpha}-ketoamide inhibitors were prepared and investigated in an HCV NS3 serine protease continuous assay (K*{sub i}). The biological activity varied substantially depending on factors such as the ring size, number of amino acid residues, number of methyl substituents, type of heteroatom in the linker, P3 residue, and configuration at the proline C-4 center. The pentapeptide inhibitors were very potent, with the C-terminal acids and amides being the most active ones (24, K*{sub i} = 8 nM). The tetrapeptides and tripeptides were less potent. Sixteen- and seventeen-membered macrocyclic compounds were equally potent, while fifteen-membered analogues were slightly less active. gem-Dimethyl substituents at the linker improved the potency of all inhibitors (the best compound was 45, K*{sub i} = 6 nM). The combination of tert-leucine at P3 and dimethyl substituents at the linker in compound 47 realized a selectivitymore » of 307 against human neutrophil elastase. Compound 45 had an IC{sub 50} of 130 nM in a cellular replicon assay, while IC{sub 50} for 24 was 400 nM. Several compounds had excellent subcutaneous AUC and bioavailability in rats. Although tripeptide compound 40 was 97% orally bioavailable, larger pentapeptides generally had low oral bioavailability. The X-ray crystal structure of compounds 24 and 45 bound to the protease demonstrated the close interaction of the macrocycle with the Ala156 methyl group and S4 pocket. The strategy of macrocyclization has been proved to be successful in improving potency (>20-fold greater than that of 1) and in structural depeptization.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. (SPRI)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1007777
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 49; Journal Issue: (3) ; 02, 2006; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; AMIDES; AMINO ACIDS; CONFIGURATION; CRYSTAL STRUCTURE; HEPATITIS; NEUTROPHILS; PROLINE; REPLICONS; RESIDUES; SERINE; TARGETS

Citation Formats

Chen, Kevin X., Njoroge, F. George, Arasappan, Ashok, Venkatraman, Srikanth, Vibulbhan, Bancha, Yang, Weiying, Parekh, Tejal N., Pichardo, John, Prongay, Andrew, Cheng, Kuo-Chi, Butkiewicz, Nancy, Yao, Nanhua, Madison, Vincent, and Girijavallabhan, Viyyoor. Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles. United States: N. p., 2008. Web. doi:10.1021/jm050820s.
Chen, Kevin X., Njoroge, F. George, Arasappan, Ashok, Venkatraman, Srikanth, Vibulbhan, Bancha, Yang, Weiying, Parekh, Tejal N., Pichardo, John, Prongay, Andrew, Cheng, Kuo-Chi, Butkiewicz, Nancy, Yao, Nanhua, Madison, Vincent, & Girijavallabhan, Viyyoor. Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles. United States. doi:10.1021/jm050820s.
Chen, Kevin X., Njoroge, F. George, Arasappan, Ashok, Venkatraman, Srikanth, Vibulbhan, Bancha, Yang, Weiying, Parekh, Tejal N., Pichardo, John, Prongay, Andrew, Cheng, Kuo-Chi, Butkiewicz, Nancy, Yao, Nanhua, Madison, Vincent, and Girijavallabhan, Viyyoor. Mon . "Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles". United States. doi:10.1021/jm050820s.
@article{osti_1007777,
title = {Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles},
author = {Chen, Kevin X. and Njoroge, F. George and Arasappan, Ashok and Venkatraman, Srikanth and Vibulbhan, Bancha and Yang, Weiying and Parekh, Tejal N. and Pichardo, John and Prongay, Andrew and Cheng, Kuo-Chi and Butkiewicz, Nancy and Yao, Nanhua and Madison, Vincent and Girijavallabhan, Viyyoor},
abstractNote = {The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It has been a target of choice for intensive drug discovery research. On the basis of an active pentapeptide inhibitor, 1, we envisioned that macrocyclization from the P2 proline to P3 capping could enhance binding to the backbone Ala156 residue and the S4 pocket. Thus, a number of P2 proline-based macrocyclic {alpha}-ketoamide inhibitors were prepared and investigated in an HCV NS3 serine protease continuous assay (K*{sub i}). The biological activity varied substantially depending on factors such as the ring size, number of amino acid residues, number of methyl substituents, type of heteroatom in the linker, P3 residue, and configuration at the proline C-4 center. The pentapeptide inhibitors were very potent, with the C-terminal acids and amides being the most active ones (24, K*{sub i} = 8 nM). The tetrapeptides and tripeptides were less potent. Sixteen- and seventeen-membered macrocyclic compounds were equally potent, while fifteen-membered analogues were slightly less active. gem-Dimethyl substituents at the linker improved the potency of all inhibitors (the best compound was 45, K*{sub i} = 6 nM). The combination of tert-leucine at P3 and dimethyl substituents at the linker in compound 47 realized a selectivity of 307 against human neutrophil elastase. Compound 45 had an IC{sub 50} of 130 nM in a cellular replicon assay, while IC{sub 50} for 24 was 400 nM. Several compounds had excellent subcutaneous AUC and bioavailability in rats. Although tripeptide compound 40 was 97% orally bioavailable, larger pentapeptides generally had low oral bioavailability. The X-ray crystal structure of compounds 24 and 45 bound to the protease demonstrated the close interaction of the macrocycle with the Ala156 methyl group and S4 pocket. The strategy of macrocyclization has been proved to be successful in improving potency (>20-fold greater than that of 1) and in structural depeptization.},
doi = {10.1021/jm050820s},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (3) ; 02, 2006,
volume = 49,
place = {United States},
year = {2008},
month = {6}
}