PTC725, an NS4B-Targeting Compound, Inhibits a Hepatitis C Virus Genotype 3 Replicon, as Predicted by Genome Sequence Analysis and Determined Experimentally

Article

Author: Tong, Xiao ; Pichardo, John ; Lahser, Frederick ; Graci, Jason D. ; Jung, Stephen P. ; Colacino, Joseph M. ; Gu, Zhengxian

ABSTRACT PTC725 is a small molecule NS4B-targeting inhibitor of hepatitis C virus (HCV) genotype (gt) 1 RNA replication that lacks activity against HCV gt2. We analyzed the Los Alamos HCV sequence database to predict susceptible/resistant HCV gt's according to the prevalence of known resistance-conferring amino acids in the NS4B protein. Our analysis predicted that HCV gt3 would be highly susceptible to the activity of PTC725. Indeed, PTC725 was shown to be active against a gt3 subgenomic replicon with a 50% effective concentration of ∼5 nM. De novo resistance selection identified mutations encoding amino acid substitutions mapping to the first predicted transmembrane region of NS4B, a finding consistent with results for PTC725 and other NS4B-targeting compounds against HCV gt1. This is the first report of the activity of an NS4B targeting compound against HCV gt3. In addition, we have identified previously unreported amino acid substitutions selected by PTC725 treatment which further demonstrate that these compounds target the NS4B first transmembrane region.

13 Mar 2014·Journal of Medicinal ChemistryQ1 · MEDICINE

Structure–Activity Relationship (SAR) Optimization of 6-(Indol-2-yl)pyridine-3-sulfonamides: Identification of Potent, Selective, and Orally Bioavailable Small Molecules Targeting Hepatitis C (HCV) NS4B

Q1 · MEDICINE

Article

Author: Zheng, Yingcong ; Li, Chunshi ; Njoroge, F. George ; Clausen, Valerie ; Mollin, Anna ; Huang, Song ; Weetall, Marla ; Almstead, Neil ; Sheedy, Josephine ; Kakarla, Ramesh ; Ren, Hongyu ; Morrill, Christie ; Graci, Jason ; Zhu, Jin ; Venkatraman, Srikanth ; Gu, Zhengxian ; Turpoff, Anthony ; Colacino, Joseph M. ; Jung, Stephen P. ; Chen, Guangming ; Karp, Gary M. ; Nomeir, Amin ; Zhang, Xiaoyan ; Lennox, William ; Zhang, Nanjing ; Lahser, Fred ; Liu, Ronggang

A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the optimal combination of substituents at the indole N-1, C-5, and C-6 positions and the sulfonamide group to limit the potential for in vivo oxidative metabolism and to achieve an acceptable pharmacokinetic profile. Compound 4t has excellent potency against the HCV 1b replicon, with an EC50 = 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. Compound 4t has an overall favorable pharmacokinetic profile with oral bioavailability values of 62%, 78%, and 18% in rats, dogs, and monkeys, respectively, as well as favorable tissue distribution properties with a liver to plasma exposure ratio of 25 in rats.

01 Jul 2013·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Identification of PTC725, an Orally Bioavailable Small Molecule That Selectively Targets the Hepatitis C Virus NS4B Protein

Q2 · MEDICINE

Article

Author: Nomeir, Amin ; Lahser, Frederick C. ; Breslin, Jamie J. ; McMonagle, Patricia ; Zhu, Jin ; Graci, Jason D. ; Colacino, Joseph M. ; Weetall, Marla ; Almstead, Neil G. ; Karp, Gary ; Xia, Ellen ; Huang, Song ; Jung, Stephen P. ; Ralston, Robert ; Liu, Shaotang ; Tong, Xiao ; Gu, Zhengxian ; Crona, James H. ; Peltz, Stuart W.

ABSTRACT While new direct-acting antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection have been approved, there is a continued need for novel antiviral agents that act on new targets and can be used in combination with current therapies to enhance efficacy and to restrict the emergence of drug-resistant viral variants. To this end, we have identified a novel class of small molecules, exemplified by PTC725, that target the nonstructural protein 4B (NS4B). PTC725 inhibited HCV 1b (Con1) replicons with a 50% effective concentration (EC 50 ) of 1.7 nM and an EC 90 of 9.6 nM and demonstrated a >1,000-fold selectivity window with respect to cytotoxicity. The compounds were fully active against HCV replicon mutants that are resistant to inhibitors of NS3 protease and NS5B polymerase. Replicons selected for resistance to PTC725 harbored amino acid substitutions F98L/C and V105M in NS4B. Anti-replicon activity of PTC725 was additive to synergistic in combination with alpha interferon or with inhibitors of HCV protease and polymerase. Immunofluorescence microscopy demonstrated that neither the HCV inhibitors nor the F98C substitution altered the subcellular localization of NS4B or NS5A in replicon cells. Oral dosing of PTC725 showed a favorable pharmacokinetic profile with high liver and plasma exposure in mice and rats. Modeling of dosing regimens in humans indicates that a once-per-day or twice-per-day oral dosing regimen is feasible. Overall, the preclinical data support the development of PTC725 for use in the treatment of chronic HCV infection.

100 Deals associated with PTC-725

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis C	Preclinical	United States	PTC Therapeutics, Inc.	-

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