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Kevin X Chen,
Charles A Lesburg,
Bancha Vibulbhan, Weiying Yang,
Tin-Yau Chan,
Srikanth Venkatraman,
Francisco Velazquez,
Qingbei Zeng,
Frank Bennett,
Gopinadhan N Anilkumar, [......],
Haiyan Pu,
Sony Agrawal,
Boris Feld,
Hsueh-Cheng Huang,
Cheng Li,
Kuo-Chi Cheng,
Neng-Yang Shih,
Joseph A Kozlowski,
Stuart B Rosenblum,
F George Njoroge
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ABSTRACT: Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 μM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.
Journal of Medicinal Chemistry 03/2012; 55(5):2089-101. · 4.80 Impact Factor
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Kevin X Chen,
Bancha Vibulbhan, Weiying Yang,
Mousumi Sannigrahi,
Francisco Velazquez,
Tin-Yau Chan,
Srikanth Venkatraman,
Gopinadhan N Anilkumar,
Qingbei Zeng,
Frank Bennet, [......],
Oleg Selyutin,
Sony Agrawal,
Boris Feld,
Hsueh-Cheng Huang,
Cheng Li,
Kuo-Chi Cheng,
Neng-Yang Shih,
Joseph A Kozlowski,
Stuart B Rosenblum,
F George Njoroge
[show abstract]
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ABSTRACT: Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 μM) and cell-based replicon (EC(50) = 0.02 μM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 μM·h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.
Journal of Medicinal Chemistry 12/2011; 55(2):754-65. · 4.80 Impact Factor
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Ashok Arasappan,
Frank Bennett,
Stephane L. Bogen,
Srikanth Venkatraman,
Melissa Blackman,
Kevin X. Chen,
Siska Hendrata,
Yuhua Huang,
Regina M. Huelgas,
Latha Nair, [......],
Paul McNamara,
Andrew Prongay,
Vincent Madison,
John J. Piwinski,
Kuo-Chi Cheng,
Richard Morrison,
Bruce Malcolm,
Xiao Tong,
Robert Ralston,
F. George Njoroge
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ABSTRACT: Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.Keywords (keywords): Hepatitis C virus NS3 serine protease inhibitor; α-ketoamide; narlaprevir; SCH 900518
02/2010;
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Kevin X Chen,
Latha Nair,
Bancha Vibulbhan, Weiying Yang,
Ashok Arasappan,
Stephane L Bogen,
Srikanth Venkatraman,
Frank Bennett,
Weidong Pan,
Melissa L Blackman,
Angela I Padilla,
Andrew Prongay,
Kuo-Chi Cheng,
Xiao Tong,
Neng-Yang Shih,
F George Njoroge
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ABSTRACT: The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC(90) by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K(i)* = 4 nM, EC(90) = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K(i)* = 4 nM, EC(90) = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
Journal of Medicinal Chemistry 03/2009; 52(5):1370-9. · 4.80 Impact Factor
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ABSTRACT: Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl-sultam cappings were selected for further SAR development. Modification at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall profile in potency and PK profile: excellent K(i)(*) of 5.3 nM and activity in replicon (EC(90)) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 microMh.
Bioorganic & medicinal chemistry letters 02/2009; 19(4):1105-9. · 2.65 Impact Factor
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[show abstract]
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ABSTRACT: Starting from a pentapeptide Hepatitis C virus NS3 protease inhibitor, a number of alpha-ketoamide inhibitors based on novel dichlorocyclopropylproline P2 core were synthesized and investigated for their HCV NS3 serine protease activity. The key intermediate 3,4-dichlorocyclopropylproline was obtained through a dichloro carbene insertion to 3,4-dehydroproline. The size of the molecules was reduced significantly through a series of truncations of the initial pentapeptide. By varying P1 side chain in length and size, potency and selectivity were improved. A variety of aliphatic carbamate and urea capping groups were examined. In general, compounds with urea cappings were more potent and selective than their carbamate counterparts. The most potent compound was a tert-butyl urea analog. Variations at P3 position were also investigated. Among the three residues incorporated, tert-leucine was clearly superior, leading to compounds that had excellent enzyme potency and selectivity. The most potent compound achieved cell-based replicon assay EC50 of 40 nM. The most promising compound of all had excellent potency in both enzyme (Ki* = 9 nM) and replicon assays (EC50 = 100 nM). Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations.
Bioorganic & medicinal chemistry 03/2008; 16(4):1874-83. · 2.82 Impact Factor
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Srikanth Venkatraman,
Stéphane L Bogen,
Ashok Arasappan,
Frank Bennett,
Kevin Chen,
Edwin Jao,
Yi-Tsung Liu,
Raymond Lovey,
Siska Hendrata,
Yuhua Huang, [......],
Walter Korfmacher,
Ronald White,
Susan Bogdanowich-Knipp,
Anastasia Pavlovsky,
Prudence Bradley,
Anil K Saksena,
Ashit Ganguly,
John Piwinski,
Viyyoor Girijavallabhan,
F George Njoroge
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ABSTRACT: Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.
Journal of Medicinal Chemistry 11/2006; 49(20):6074-86. · 5.25 Impact Factor
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Kevin X Chen,
F George Njoroge,
Ashok Arasappan,
Srikanth Venkatraman,
Bancha Vibulbhan, Weiying Yang,
Tejal N Parekh,
John Pichardo,
Andrew Prongay,
Kuo-Chi Cheng,
Nancy Butkiewicz,
Nanhua Yao,
Vincent Madison,
Viyyoor Girijavallabhan
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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(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(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(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(50) of 130 nM in a cellular replicon assay, while IC(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.
Journal of Medicinal Chemistry 02/2006; 49(3):995-1005. · 5.25 Impact Factor
