Preclinical Characterization of the Novel HCV NS3 Protease Inhibitor GS-9256

Yang, Huiling; Yang, Chi‐Cheng; Wang, Yujin; Rhodes, Gerry; Robinson, Margaret; Cheng, Guofeng; Qi, Xiaoping; Mo, Hongmei; Yang, Tian; Pakdaman, Rowchanak; Sheng, X. Christopher; Kim, Choung U.; Delaney, William E.

doi:10.3851/imp3132

Cited by 3 publications

(2 citation statements)

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“…Overall, substitution with fluorine, methoxy, and methyl groups was well tolerated, with a preference for ortho-disubstitution probably due to the potential “shielding effect” on the polar phosphinic acid group. GS-9256 ( 42 ) (Figure ) emerged for the best outcomes of potency ( K i of 0.089 nM, EC 50 of 20 nM) and PK profile (bioavailability of 22% in dogs) of this series and entered the phase II clinical trials . However, data from clinical studies limited further development of this drug candidate.…”

Section: Hcv Ns3 Pis: Development Of Inhibitors Of First Second and T...mentioning

confidence: 99%

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Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

Martino,

Petri,

De Rosa

2024

J. Med. Chem.

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Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals. These regimens include drugs targeting different stages of the HCV life cycle. However, the emergence of viral resistance remains a big concern. The design of peptidomimetic inhibitors (PIs) able to fit and fill the conserved substrate envelope region within the active site helped avoid contact with the vulnerable sites of the most common resistance-associated substitutions Arg155, Ala156, and Asp168. Herein, we give an overview of HCV NS3 PIs discovered during the past decade, and we deeply discuss the rationale behind the structural optimization efforts essential to achieve pangenotypic activity.

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Section: Hcv Ns3 Pis: Development Of Inhibitors Of First Second and T...mentioning

confidence: 99%

“…GS-9256 (42) (Figure 15) emerged for the best outcomes of potency (K i of 0.089 nM, EC 50 of 20 nM) and PK profile (bioavailability of 22% in dogs) of this series and entered the phase II clinical trials. 136 However, data from clinical studies limited further development of this drug candidate.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%