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Timothy D Cushing,
Vijay Baichwal,
Karen Berry,
Roland Billedeau, Viola Bordunov,
Chris Broka,
Michelle F Browner,
Mario Cardozo,
Peng Cheng,
David Clark, [......],
Eric B Sjogren,
Marie-Louise Smith,
Francisco X Talamas,
George Tonn,
Keith M Walker,
Nigel P C Walker,
Holger Wesche,
Chris Whitehead,
Matt Wright,
Juan C Jaen
[show abstract]
[hide abstract]
ABSTRACT: A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Bioorganic & medicinal chemistry letters 10/2010; 21(1):423-6. · 2.65 Impact Factor
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Timothy D Cushing,
Vijay Baichwal,
Karen Berry,
Roland Billedeau, Viola Bordunov,
Chris Broka,
Mario Cardozo,
Peng Cheng,
David Clark,
Stacie Dalrymple, [......],
Eric B Sjogren,
Marie-Louise Smith,
Francisco X Talamas,
George Tonn,
Keith M Walker,
Nigel P C Walker,
Holger Wesche,
Chris Whitehead,
Matt Wright,
Michelle F Browner
[show abstract]
[hide abstract]
ABSTRACT: A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
Bioorganic & medicinal chemistry letters 10/2010; 21(1):417-22. · 2.65 Impact Factor
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Jeffrey A Campbell, Viola Bordunov,
Chris A Broka,
Michelle F Browner,
James M Kress,
Tara Mirzadegan,
Chakk Ramesha,
Bong F Sanpablo,
Russell Stabler,
Patricia Takahara,
Armando Villasenor,
Keith A M Walker,
Jin-Hai Wang,
Mary Welch,
Paul Weller
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[hide abstract]
ABSTRACT: The introduction of 3-arylmethyl, 3-aryloxy and 3-arylthio moieties into a 6-methylsulfonylindole framework using rational drug design led to potent, selective COX-2 inhibitors having efficacy in a rat carrageenan air pouch model. Incorporation of a conformationally more rigid 3-aroyloxy substituent onto the 6-methylsulfonylindole scaffold led to selective, but considerably less potent COX-2 inhibitors. Variation of the hydrophilicity and size of the indole 2-substituent of 3-arylthio-6-methylsulfonylindole inhibitors led to modulation of the COX-2 human whole blood (HWB) potency and selectivity.
Bioorganic & Medicinal Chemistry Letters 10/2004; 14(18):4741-5. · 2.55 Impact Factor
