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. 2017 Jan 31;8(2):251-255.
doi: 10.1021/acsmedchemlett.6b00479. eCollection 2017 Feb 9.

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates

Pan Li  1 , Warren Dorsch  1 , David J Lauffer  1 , Darius Bilimoria  1 , Nathalie Chauret  2 , John J Court  1 , Sanjoy Kumar Das  2 , Francois Denis  2 , Nagraj Mani  1 , Suganthini Nanthakumar  1 , Olivier Nicolas  2 , B Govinda Rao  1 , Steven Ronkin  1 , Subajini Selliah  2 , Rebecca S Shawgo  1 , Ralph Stearns  1 , Qing Tang  1 , Nathan D Waal  1 , Jeremy Green  1
Affiliations

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates

Pan Li et al. ACS Med Chem Lett. .

Abstract

Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound 2, a molecule with comparable potency and an improved physicochemical profile relative to 1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by 12f, provided 3-5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure-activity relationships, in vitro ADME characterization, and in vivo evaluation of this novel series are discussed.

Keywords: Lomibuvir; NS5B; antiviral activity; hepatitis C; non-nucleoside; polymerase.

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Conflict of interest statement

The authors declare the following competing financial interest(s): All of the authors of this manuscript are current or former employees of Vertex Pharmaceuticals.

Figures

Figure 1
Figure 1
Model of 1 bound to HCV genotype 1b NS5B showing the proximity of the trans-4-hydroxycyclohexyl ring to Arg501.
Scheme 1
Scheme 1. General Synthesis of Compounds 12a–12f
Reaction conditions: (a) ethyl 1,3-dioxoisoindoline-2-carboxylate, Na2CO3, H2O, RT; (b) NaH, MeI, DMF, 0 °C; (c) NH2NH2, MeOH, RT; (d) Pd(OAc)2, BINAP, Cs2CO3, toluene, 90 °C; (e) trans-4-methylcyclohexylcarbonyl chloride, pyridine, DCE, reflux; (f) LiOH, THF, H2O, RT
Figure 2
Figure 2
Mean plasma and tissue concentration–time profile of compound 12f in male Sprague–Dawley rats.
See this image and copyright information in PMC

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