Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles

Lampa, Anna; Alogheli, Hiba; Ehrenberg, Angelica E.; Åkerblom, Eva; Svensson, Richard; Artursson, Per; Danielson, U. Helena; Karlén, Anders; Sandström, Anna

doi:10.1016/j.bmc.2014.10.010

Cited by 6 publications

(3 citation statements)

References 59 publications

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“…Unfortunately, compounds of this class suffered from poor PK profile and low cell permeability, thus explaining the poor inhibitory efficiency in the replicon assays …”

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

confidence: 99%

“…Unfortunately, compounds of this class suffered from poor PK profile and low cell permeability, thus explaining the poor inhibitory efficiency in the replicon assays. 156 On the same P2 pyrimidinyloxy-Phg linear precursor, other macrocyclization strategies (P2−P4, P2−P1′, P3−P1′) together with truncation studies of the P4 and P1′ groups were evaluated, and inhibitors with low risk for high first pass metabolism, good apparent intestinal permeability, and moderate solubility were obtained. 154 3.2.5.…”

Section: Journal Of Medicinal Chemistrymentioning

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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“…Unfortunately, compounds of this class suffered from poor PK profile and low cell permeability, thus explaining the poor inhibitory efficiency in the replicon assays …”

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

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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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show abstract

“…N-Acylsulfonamides are typically synthesized by the activation of carboxylic acids using 1,1′-carbonyldiimidazole (CDI) 184,185 or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC). 163,186 However, this approach requires a stoichiometric amount of these activating agents, which can be a limitation.…”

Section: Synthesis Of N-acylsulfonamides Through N-acylation Of Sulfomentioning

confidence: 99%

Recent Functionalizations of Primary Sulfonamides

Chen

2016

Synthesis

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Sulfonamides are common building blocks in organic synthesis. They have a wide range of medical applications. This review aims to delineate recent efforts towards the functionalization of primary sulfonamides during last three years and to provide an overview of the synthesis of N-alkylated, N-acylated, and N-arylated sulfonamides from primary sulfonamides. Among other reactions, the sulfonamide-directed C-H functionalization is highlighted.

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The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

Herndon

2016

Coordination Chemistry Reviews

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Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles

Cited by 6 publications

References 59 publications

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

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

Recent Functionalizations of Primary Sulfonamides

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

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