Structure-activity relationship and improved hydrolytic stability of pyrazole derivatives that are allosteric inhibitors of West Nile Virus NS2B-NS3 proteinase.
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.
Sidique
Shyama
S
Conrad Prebys Center for Chemical Genomics, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Shiryaev
Sergey A
SA
Ratnikov
Boris I
BI
Herath
Ananda
A
Su
Ying
Y
Strongin
Alex Y
AY
Cosford
Nicholas D P
ND
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
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
Ann N Y Acad Sci. 2001 Dec;951:25-37
11797781
Lancet Infect Dis. 2002 Sep;2(9):519-29
12206968
Antimicrob Agents Chemother. 2008 Sep;52(9):3385-93
18606844
Bioorg Med Chem Lett. 2007 Sep 1;17(17):4761-6
17656088
J Biol Chem. 2007 Apr 27;282(17):12883-92
17337448
PLoS Negl Trop Dis. 2009;3(1):e356
19159012
Assay Drug Dev Technol. 2007 Dec;5(6):737-50
18181690
Biochemistry. 2008 Nov 11;47(45):11763-70
18855422
J Med Chem. 2008 Sep 25;51(18):5714-21
18729351
Arch Virol. 2005 Apr;150(4):637-57
15662484
Curr Med Chem. 2008;15(27):2771-84
18991636