title: Structure-activity relationship and improved hydrolytic stability of pyrazole derivatives that are allosteric inhibitors of West Nile Virus NS2B-NS3 proteinase.
abstract: West Nile Virus (WNV) is a potentially deadly mosquito-borne flavivirus which has spread rapidly throughout the world. Currently there is no effective vaccine against flaviviral infections. We previously reported the identification of pyrazole ester derivatives as allosteric inhibitors of WNV NS2B-NS3 proteinase. These compounds degrade rapidly in pH 8 buffer with a half life of 1-2h. We now report the design, synthesis and in vitro evaluation of pyrazole derivatives that are inhibitors of WNV NS2B-NS3 proteinase with greatly improved stability in the assay medium.
authors.affiliation: Conrad Prebys Center for Chemical Genomics, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Shyama
authors.initials: S
authors.lastname: Sidique
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Shiryaev
authors.forename: Boris I
authors.initials: BI
authors.lastname: Ratnikov
authors.forename: Ananda
authors.initials: A
authors.lastname: Herath
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000494:Allosteric Regulation; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014901:West Nile Fever / Q000188:drug therapy; D014902:West Nile virus / Q000187:drug effects*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011720:Pyrazoles; D020365:RNA Helicases; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
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