Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.

Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. Research Abstract Details 

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Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. Abstract Text:

Chih-Ming Chen,Yupeng He,Liangjun Lu,Hock Ben Lim,Rakesh L Tripathi,Tim Middleton,Lisa E Hernandez,David W A Beno,Michelle A Long,Warren M Kati,Todd D Bosse,Daniel P Larson,Rolf Wagner,Robert E Lanford,William E Kohlbrenner,Dale J Kempf,Tami J Pilot-Matias,Akhteruzzaman Molla,Chih-Ming Chen,Yupeng He,Liangjun Lu,Hock Ben Lim,Rakesh L Tripathi,Tim Middleton,Lisa E Hernandez,David W A Beno,Michelle A Long,Warren M Kati,Todd D Bosse,Daniel P Larson,Rolf Wagner,Robert E Lanford,William E Kohlbrenner,Dale J Kempf,Tami J Pilot-Matias,Akhteruzzaman Molla,

A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.

Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. Publishing Authors By Initials

CM Chen,Y He,L Lu,HB Lim,RL Tripathi,T Middleton,LE Hernandez,DW Beno,MA Long,WM Kati,TD Bosse,DP Larson,R Wagner,RE Lanford,WE Kohlbrenner,DJ Kempf,TJ Pilot-Matias,A Molla,CM Chen,Y He,L Lu,HB Lim,RL Tripathi,T Middleton,LE Hernandez,DW Beno,MA Long,WM Kati,TD Bosse,DP Larson,R Wagner,RE Lanford,WE Kohlbrenner,DJ Kempf,TJ Pilot-Matias,A Molla,

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Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Antimicrobial agents and chemotherapy

VOLUME: 51

Page Numbers: 4290-6

Journal Abbreviation: Antimicrob. Agents Chemother.

ISSN: 0066-4804

DAY: 1

MONTH: 10

YEAR: 2007

Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model. Information

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LANGUAGE: eng

NlmUniqueID: 315061

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AFFILIATION: Abbott Laboratories, Dept. R43H, Building AP52N, 200 Abbott Park Rd., Abbott Park, IL 60064. tami.pilot-matias@abbott.com.

Country: United States

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MEDLINETA: Antimicrob Agents Chemother

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