Toward the Back-Up of Boceprevir (SCH 503034): Discovery of New Extended P4-Capped Ketoamide Inhibitors of Hepatitis C Virus NS3 Serine Protease with Improved Potency and Pharmacokinetic Profiles

被引：23

作者：

Bogen, Stephane L. ^{[1
]}

Pan, Weidong ^{[1
]}

Ruan, Sumei ^{[1
]}

Nair, Latha G. ^{[1
]}

Arasappan, Ashok ^{[1
]}

Bennett, Frank ^{[1
]}

Chen, Kevin X. ^{[1
]}

Jao, Edwin ^{[1
]}

Venkatraman, Srikanth ^{[1
]}

Vibulbhan, Bancha ^{[1
]}

Liu, Rong ^{[1
]}

Cheng, Kuo-Chi ^{[1
]}

Guo, Zhuyan ^{[1
]}

Tong, Xiao ^{[1
]}

Saksena, Anil K. ^{[1
]}

Girijavallabhan, Viyyoor ^{[1
]}

Njoroge, F. George ^{[1
]}

机构：

[1] Schering Plough Res Inst, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 12期

关键词：

MACROCYCLIC INHIBITORS; ALPHA-KETOAMIDES; REPLICATION; CHALLENGES; SCH-503034; RIBAVIRIN; P1;

D O I：

10.1021/jm801632a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P-4 pocket and optimization of the P-1' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P-4-capped inhibitors were also found to have improved PK profile.

引用

页码：3679 / 3688

页数：10

共 41 条

[21]

Mederacke I, 2009, CURR OPIN INVEST DR, V10, P181

[22]

Narjes F, 2003, EXPERT OPIN INV DRUG, V12, P153, DOI 10.1517/13543784.12.2.153

[23] Capped dipeptide phenethylamide inhibitors of the HCVNS3 protease [J].

Nizi, E ;

Koch, U ;

Ontoria, JM ;

Marchetti, A ;

Narjes, F ;

Malancona, S ;

Matassa, VG ;

Gardelli, C .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (09) :2151-2154

[24] Challenges in modern drug discovery: A case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection [J].

Njoroge, F. George ;

Chen, Kevin X. ;

Shih, Neng-Yang ;

Piwinski, John J. .

ACCOUNTS OF CHEMICAL RESEARCH, 2008, 41 (01) :50-59

[25] Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease [J].

Perni, RB ;

Almquist, SJ ;

Byrn, RA ;

Chandorkar, G ;

Chaturvedi, PR ;

Courtney, LF ;

Decker, CJ ;

Dinehart, K ;

Gates, CA ;

Harbeson, SL ;

Heiser, A ;

Kalkeri, G ;

Kolaczkowski, E ;

Lin, K ;

Luong, YP ;

Rao, BG ;

Taylor, WP ;

Thomson, JA ;

Tung, RD ;

Wei, YY ;

Kwong, AD ;

Lin, C .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2006, 50 (03) :899-909

[26] Inhibitors of hepatitis C virus NS3•4A protease.: Part 3:: P2 proline variants [J].

Perni, RB ;

Farmer, LJ ;

Cottrell, KM ;

Court, JJ ;

Courtney, LF ;

Deininger, DD ;

Gates, CA ;

Harbeson, SL ;

Kim, JL ;

Lin, C ;

Lin, K ;

Luong, YP ;

Maxwell, JP ;

Murcko, MA ;

Pitlik, J ;

Rao, BG ;

Schairer, WC ;

Tung, RD ;

Van Drie, JH ;

Wilson, K ;

Thomson, JA .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (08) :1939-1942

[27] A CARBONYL OLEFINATION REACTION USING SILYL-SUBSITUTED ORGANOMETALLIC COMPOUNDS [J].

PETERSON, DJ .

JOURNAL OF ORGANIC CHEMISTRY, 1968, 33 (02) :780-&

[28] SYNTHESIS OF NUCLEOSIDE-5' ALDEHYDES [J].

PFITZNER, KE ;

MOFFATT, JG .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1963, 85 (19) :3027-&

[29] P1 phenethyl peptide boronic acid inhibitors of HCVNS3 protease [J].

Priestley, ES ;

De Lucca, I ;

Ghavimi, B ;

Erickson-Viitanen, S ;

Decicco, CP .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (21) :3199-3202

[30] Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350 [J].

Raboisson, Pierre ;

de Kock, Herman ;

Rosenquist, Asa ;

Nilsson, Magnus ;

Salvador-Oden, Lourdes ;

Lin, Tse-I ;

Roue, Natalie ;

Ivanov, Vladimir ;

Wahling, Horst ;

Wickstrom, Kristina ;

Hamelink, Elizabeth ;

Edlund, Michael ;

Vrang, Lotta ;

Vendeville, Sandrine ;

Van de Vreken, Wim ;

McGowan, David ;

Tahri, Abdellah ;

Hu, Lili ;

Boutton, Carlo ;

Lenz, Oliver ;

Delouvroy, Frederic ;

Pille, Geert ;

Surleraux, Dominique ;

Wigerinck, Piet ;

Samuelsson, Bertil ;

Simmen, Kenneth .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (17) :4853-4858

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