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Xianyun Jiao,
David J Kopecky,
Jinsong Liu,
Jinqian Liu, Juan C Jaen,
Mario G Cardozo,
Rajiv Sharma,
Nigel Walker,
Holger Wesche,
Shyun Li,
Ellyn Farrelly,
Shou-Hua Xiao,
Zhulun Wang,
Frank Kayser
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ABSTRACT: Two classes of ACK1 inhibitors, 4,5,6-trisubstituted furo[2,3-d]pyrimidin4-amines and 4,5,6-trisubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amines, were discovered and evaluated as ACK1 inhibitors. Further structural refinement led to the identification of potent and selective dithiolane inhibitor 37.
Bioorganic & medicinal chemistry letters 08/2012; 22(19):6212-7. · 2.65 Impact Factor
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ABSTRACT: A novel series of benzenesulfonanilide derivatives of 11β-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11β-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).
Bioorganic & medicinal chemistry letters 04/2012; 22(11):3786-90. · 2.65 Impact Factor
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Daqing Sun,
Zhulun Wang,
Seb Caille,
Michael DeGraffenreid,
Felix Gonzalez-Lopez de Turiso,
Randall Hungate, Juan C Jaen,
Ben Jiang,
Lisa D Julian,
Ron Kelly, [......],
Jacob Kaizerman,
Yosup Rew,
Athena Sudom,
Hua Tu,
Stefania Ursu,
Nigel Walker,
Maren Willcockson,
Xuelei Yan,
Qiuping Ye,
Jay P Powers
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ABSTRACT: The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Bioorganic & medicinal chemistry letters 01/2011; 21(1):405-10. · 2.65 Impact Factor
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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
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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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Xuelei Yan,
Zhulun Wang,
Athena Sudom,
Mario Cardozo,
Michael DeGraffenreid,
Yongmei Di,
Pingchen Fan,
Xiao He, Juan C Jaen,
Marc Labelle, [......],
Ji Ma,
Dustin McMinn,
Shichang Miao,
Daqing Sun,
Liang Tang,
Hua Tu,
Stefania Ursu,
Nigel Walker,
Qiuping Ye,
Jay P Powers
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ABSTRACT: In this communication, human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11β-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Bioorganic & medicinal chemistry letters 09/2010; 20(23):7071-5. · 2.65 Impact Factor
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Daqing Sun,
Zhulun Wang,
Mario Cardozo,
Rebekah Choi,
Michael Degraffenreid,
Yongmei Di,
Xiao He, Juan C Jaen,
Marc Labelle,
Jinsong Liu,
Ji Ma,
Shichang Miao,
Athena Sudom,
Liang Tang,
Hua Tu,
Stefania Ursu,
Nigel Walker,
Xuelei Yan,
Qiuping Ye,
Jay P Powers
[show abstract]
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ABSTRACT: The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.
Bioorganic & medicinal chemistry letters 02/2009; 19(5):1522-7. · 2.65 Impact Factor
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Yosup Rew,
Dustin L McMinn,
Zhulun Wang,
Xiao He,
Randall W Hungate, Juan C Jaen,
Athena Sudom,
Daqing Sun,
Hua Tu,
Stefania Ursu,
Elisia Villemure,
Nigel P C Walker,
Xuelei Yan,
Qiuping Ye,
Jay P Powers
[show abstract]
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ABSTRACT: Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
Bioorganic & medicinal chemistry letters 02/2009; 19(6):1797-801. · 2.65 Impact Factor
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David J Kopecky,
Xiaolin Hao,
Yi Chen,
Jiasheng Fu,
XianYun Jiao, Juan C Jaen,
Mario G Cardozo,
Jinsong Liu,
Zhulun Wang,
Nigel P C Walker,
Holger Wesche,
Shyun Li,
Ellyn Farrelly,
Shou-Hua Xiao,
Frank Kayser
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ABSTRACT: A new series of pyrazolo[3,4-d]pyrimidine-3,6-diamines was designed and synthesized as potent and selective inhibitors of the nonreceptor tyrosine kinase, ACK1. These compounds arose from efforts to rigidify an earlier series of N-aryl pyrimidine-5-carboxamides. The synthesis and structure-activity relationships of this new series of inhibitors are reported. The most promising compounds were also profiled for their pharmacokinetic properties.
Bioorganic & medicinal chemistry letters 01/2009; 18(24):6352-6. · 2.65 Impact Factor
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Hua Tu,
Jay P Powers,
Jinsong Liu,
Stefania Ursu,
Athena Sudom,
Xuelei Yan,
Haoda Xu,
David Meininger,
Michael Degraffenreid,
Xiao He, Juan C Jaen,
Daqing Sun,
Marc Labelle,
Hiroshi Yamamoto,
Bei Shan,
Nigel P C Walker,
Zhulun Wang
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ABSTRACT: 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the NADPH dependent interconversion of inactive cortisone to active cortisol. Excess 11beta-HSD1 or cortisol leads to insulin resistance and metabolic syndrome in animal models and in humans. Inhibiting 11beta-HSD1 activity signifies a promising therapeutic strategy in the treatment of Type 2 diabetes and related diseases. Herein, we report two highly potent and selective small molecule inhibitors of human 11beta-HSD1. While compound 1, a sulfonamide, functions as a simple substrate competitive inhibitor, compound 2, a triazole, shows the kinetic profile of a mixed inhibitor. Co-crystal structures reveal that both compounds occupy the 11beta-HSD1 catalytic site, but present distinct molecular interactions with the protein. Strikingly, compound 2 interacts much closer to the cofactor NADP+ and likely modifies its binding. Together, the structural and kinetic analyses demonstrate two distinctive molecular inhibition mechanisms, providing valuable information for future inhibitor design.
Bioorganic & medicinal chemistry 09/2008; 16(19):8922-31. · 2.82 Impact Factor
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Lisa D Julian,
Zhulun Wang,
Tracy Bostick,
Seb Caille,
Rebekah Choi,
Michael DeGraffenreid,
Yongmei Di,
Xiao He,
Randall W Hungate, Juan C Jaen, [......],
Dustin McMinn,
Yosup Rew,
Athena Sudom,
Daqing Sun,
Hua Tu,
Stefania Ursu,
Nigel Walker,
Xuelei Yan,
Qiuping Ye,
Jay P Powers
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ABSTRACT: We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
Journal of Medicinal Chemistry 08/2008; 51(13):3953-60. · 4.80 Impact Factor
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Daqing Sun,
Zhulun Wang,
Yongmei Di, Juan C Jaen,
Marc Labelle,
Ji Ma,
Shichang Miao,
Athena Sudom,
Liang Tang,
Craig S Tomooka,
Hua Tu,
Stefania Ursu,
Nigel Walker,
Xuelei Yan,
Qiuping Ye,
Jay P Powers
[show abstract]
[hide abstract]
ABSTRACT: High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM).
Bioorganic & medicinal chemistry letters 07/2008; 18(12):3513-6. · 2.65 Impact Factor
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ABSTRACT: High-throughput screening of a small-molecule compound library resulted in the identification of a novel series of N-acyl 2-aminobenzimidazoles that are potent inhibitors of interleukin-1 receptor-associated kinase-4.
Bioorganic & Medicinal Chemistry Letters 07/2006; 16(11):2842-5. · 2.55 Impact Factor
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Jay P Powers,
Derek E Piper,
Yang Li,
Veronica Mayorga,
John Anzola,
James M Chen, Juan C Jaen,
Gary Lee,
Jinqian Liu,
M Greg Peterson,
George R Tonn,
Qiuping Ye,
Nigel P C Walker,
Zhulun Wang
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[hide abstract]
ABSTRACT: Novel non-nucleoside inhibitors of the HCV RNA polymerase (NS5b) with sub-micromolar biochemical potency have been identified which are selective for the inhibition of HCV NS5b over other polymerases. The structures of the complexes formed between several of these inhibitors and HCV NS5b were determined by X-ray crystallography, and the inhibitors were found to bind in an allosteric binding site separate from the active site. Structure-activity relationships and structural studies have identified the mechanism of action for compounds in this series, several of which possess drug-like properties, as unique, reversible, covalent inhibitors of HCV NS5b.
Journal of Medicinal Chemistry 03/2006; 49(3):1034-46. · 5.25 Impact Factor
