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Discovery of a β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. 2010
Michael J Sofia, and
Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540, USA. michael.sofia@pharmasset.com
Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2'-Deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.
Related Publications
Michael J Sofia, and
Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
May 2011,
The Journal of organic chemistry,
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Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
January 2018,
European journal of medicinal chemistry,
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Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
July 2017,
Scientific reports,
Michael J Sofia, and
Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
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Phillip A Furman
August 2017,
Bioorganic & medicinal chemistry letters,
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Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
June 2012,
Antimicrobial agents and chemotherapy,
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Dhanapalan Nagarathnam, and
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P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
May 2019,
Journal of medicinal chemistry,
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Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
February 2019,
Bioorganic & medicinal chemistry,
Michael J Sofia, and
Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
November 2020,
Antimicrobial agents and chemotherapy,
Michael J Sofia, and
Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
Michael J Otto, and
Phillip A Furman
November 2010,
Acta crystallographica. Section C, Crystal structure communications,
Michael J Sofia, and
Donghui Bao, and
Wonsuk Chang, and
Jinfa Du, and
Dhanapalan Nagarathnam, and
Suguna Rachakonda, and
P Ganapati Reddy, and
Bruce S Ross, and
Peiyuan Wang, and
Hai-Ren Zhang, and
Shalini Bansal, and
Christine Espiritu, and
Meg Keilman, and
Angela M Lam, and
Holly M Micolochick Steuer, and
Congrong Niu, and
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