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4 results on '"Cripps, Stephan"'

1. The development and SAR of pyrrolidine carboxamide 11β-HSD1 inhibitors

Author

Michele Yang, Ganesh B. Bhat, Jacqui Elizabeth Hoffman, Andrea Fanjul, Stan Kupchinsky, Jacques Ermolieff, Klaus Ruprecht Dress, Cheng Hengmiao, Phuong Le, Jean Joo Matthews, Sajiv Krishnan Nair, Paul A. Rejto, T.A. Pauly, Evan Walters, Jocelyn Herrera, Christopher Ronald Smith, Martin Paul Edwards, Bridget Mccarthy Cole, Christine Loh, Cripps Stephan James, Natilie Hosea, and Paderes Genevieve Deguzman

Subjects
Pyrrolidines, medicine.drug_class, Stereochemistry, Guinea Pigs, Clinical Biochemistry, Pharmaceutical Science, 11β hsd1, Adamantane, Carboxamide, Biochemistry, Pyrrolidine, Mice, Structure-Activity Relationship, chemistry.chemical_compound, In vivo, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Drug Discovery, medicine, Animals, Humans, Hypoglycemic Agents, Enzyme Inhibitors, Molecular Biology, chemistry.chemical_classification, Chemistry, Organic Chemistry, Highly selective, Amides, In vitro, Enzyme, Microsomes, Liver, Molecular Medicine, Cortisone, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract

The design and development of a series of highly selective pyrrolidine carboxamide 11β-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11β-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11β-HSD1 selective inhibitor 42.

Published
2010

2. N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275

Author

Cripps Stephan James, Thomas A. Pauly, Natilie Hosea, Martin Paul Edwards, Sajiv Krishnan Nair, Arturo Castro, Jacques Ermolieff, Theodore O. Johnson, Andrea Fanjul, Jean Joo Matthews, Yong Wang, Michael Siu, Amy LaPaglia, Jennifer E. Vogel, and Taylor Wendy Dianne

Subjects
Clinical Biochemistry, Aminopyridines, Pharmaceutical Science, Dehydrogenase, Crystallography, X-Ray, Biochemistry, Isozyme, Cell Line, Structure-Activity Relationship, Cricetinae, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Drug Discovery, medicine, Animals, Humans, Computer Simulation, Enzyme Inhibitors, Molecular Biology, chemistry.chemical_classification, Sulfonamides, Organic Chemistry, Biological activity, Ligand (biochemistry), Rats, Enzyme, chemistry, Lipophilic efficiency, Drug Design, Molecular Medicine, Cortisone, hormones, hormone substitutes, and hormone antagonists, Glucocorticoid, medicine.drug
Abstract

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.

Published
2009

3. The development and SAR of pyrrolidine carboxamide 11β-HSD1 inhibitors

Author

Cheng, Hengmiao, Hoffman, Jacqui, Le, Phuong, Nair, Sajiv K., Cripps, Stephan, Matthews, Jean, Smith, Christopher, Yang, Michele, Kupchinsky, Stan, Dress, Klaus, Edwards, Martin, Cole, Bridget, Walters, Evan, Loh, Christine, Ermolieff, Jacques, Fanjul, Andrea, Bhat, Ganesh B., Herrera, Jocelyn, Pauly, Tom, and Hosea, Natilie

Subjects
*PYRROLIDINE, *ENZYME inhibitors, *CORTISONE, *ENZYME activation, *DIABETES
Abstract

Abstract: The design and development of a series of highly selective pyrrolidine carboxamide 11β-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11β-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11β-HSD1 selective inhibitor 42. [Copyright &y& Elsevier]

Published
2010
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4. N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275

Author

Siu, Michael, Johnson, Theodore O., Wang, Yong, Nair, Sajiv K., Taylor, Wendy D., Cripps, Stephan J., Matthews, Jean J., Edwards, Martin P., Pauly, Thomas A., Ermolieff, Jacques, Castro, Arturo, Hosea, Natilie A., LaPaglia, Amy, Fanjul, Andrea N., and Vogel, Jennifer E.

Subjects
*DRUG development, *SULFONAMIDES, *STEROIDS, *DEHYDROGENASES, *ENZYME inhibitors, *DIABETES, *CORTISONE
Abstract

Abstract: N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275. [Copyright &y& Elsevier]

Published
2009
Full Text
View/download PDF

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