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ABSTRACT: 3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD1). They were shown to be active in the mouse in vivo pharmacodynamic model (PD) for HSD1 but exhibited a potent off-target activation of the Pregnane X Receptor (PXR). SAR studies and synthesis of analogs that led to the discovery of a selective HSD1 inhibitor are described in detail.
Bioorganic & medicinal chemistry letters 02/2011; 21(7):2141-5. · 2.65 Impact Factor
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Yuping Zhu,
Steven H Olson,
Anne Hermanowski-Vosatka,
Steven Mundt,
Kashmira Shah,
Marty Springer,
Rolf Thieringer,
Samuel Wright,
Jianying Xiao, Hratch Zokian,
James M Balkovec
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ABSTRACT: 4-Methyl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They were active in vitro and in an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented.
Bioorganic & medicinal chemistry letters 07/2008; 18(11):3405-11. · 2.65 Impact Factor
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Yuping Zhu,
Steven H Olson,
Donald Graham,
Gool Patel,
Anne Hermanowski-Vosatka,
Steven Mundt,
Kashmira Shah,
Marty Springer,
Rolf Thieringer,
Samuel Wright,
Jianying Xiao, Hratch Zokian,
Jasminka Dragovic,
James M Balkovec
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ABSTRACT: 3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic profile significantly. The synthesis and structure-activity relationships are presented.
Bioorganic & medicinal chemistry letters 07/2008; 18(11):3412-6. · 2.65 Impact Factor
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Susan D Aster,
Donald W Graham,
Divya Kharbanda,
Gool Patel,
Mitree Ponpipom,
Gina M Santorelli,
Michael J Szymonifka,
Steven S Mundt,
Kashmira Shah,
Marty S Springer,
Rolf Thieringer,
Anne Hermanowski-Vosatka,
Samuel D Wright,
Jianying Xiao, Hratch Zokian,
James M Balkovec
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ABSTRACT: 3-Aryl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They are active in both in vitro and an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented.
Bioorganic & medicinal chemistry letters 06/2008; 18(9):2799-804. · 2.65 Impact Factor