1. Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors
- Author
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Marlys Hammond, David G. Washburn, Angela Smallwood, Tram H. Hoang, Nicholas J. Laping, Rebecca Trejo, Hiroko Nakamura, James S. Frazee, Martha S. Head, Scott K. Thompson, Kendra E. Hightower, Charlene Wu, Rakesh Nagilla, Jaclyn R. Patterson, Melanie Nord, Walter Trizna, Baoguang Zhao, Sharada Manns, Leonard M. Azzarano, and Christine G. Schnackenberg
- Subjects
Stereochemistry ,Carboxylic acid ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Glucuronidation ,Molecular Conformation ,Pharmaceutical Science ,Administration, Oral ,Biological Availability ,Protein Serine-Threonine Kinases ,Biochemistry ,Immediate-Early Proteins ,chemistry.chemical_compound ,Acetic acid ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Glucuronic Acid ,Drug Discovery ,Animals ,Carboxylate ,Enzyme Inhibitors ,Molecular Biology ,Glucocorticoids ,Protein Kinase Inhibitors ,Benzoic acid ,chemistry.chemical_classification ,biology ,Bicyclic molecule ,Organic Chemistry ,Glucuronic acid ,Rats ,chemistry ,Models, Chemical ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine - Abstract
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.
- Published
- 2009