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Your search keyword '"Walter Trizna"' showing total 3 results
Start Over Author "Walter Trizna" Journal bioorganicmedicinal chemistry letters
3 results on '"Walter Trizna"'

1. Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors

Author

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

2. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

Author

Eugene T. Grygielko, Shawn P. Williams, Lindsay E. Glace, Jeffrey D. Bray, Chaya Duraiswami, James S. Frazee, Kevin P. Madauss, David G. Washburn, Tram H. Hoang, Leahann Lapinski, Walter Trizna, Nicholas J. Laping, and Scott K. Thompson

Subjects
Agonist, Pyrrolidines, medicine.drug_class, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, Crystallography, X-Ray, Biochemistry, Partial agonist, Pyrrolidine, chemistry.chemical_compound, Drug Discovery, Progesterone receptor, medicine, Animals, Computer Simulation, Molecular Biology, Hormone binding protein, Binding Sites, Organic Chemistry, Rational design, Protein Structure, Tertiary, Rats, chemistry, Nuclear receptor, Estrogen, Drug Design, Models, Animal, Molecular Medicine, Receptors, Progesterone
Abstract

Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

Published
2009

3. Synthesis and SAR of amino acid-derived heterocyclic progesterone receptor full and partial agonists

Author

Jaclyn R. Patterson, Scott K. Thompson, Harvey E. Fries, Eugene T. Grygielko, Walter Trizna, Tram H. Hoang, Jeffrey D. Bray, Nicholas J. Laping, Douglas J. Minick, Melanie Nord, Lindsay E. Glace, Rakesh Nagilla, Marlys Hammond, Sharada Manns, and David G. Washburn

Subjects
Agonist, medicine.drug_class, Stereochemistry, Clinical Biochemistry, Triazole, Pharmaceutical Science, Tetrazoles, Biochemistry, Chemical synthesis, Partial agonist, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Progesterone receptor, medicine, Structure–activity relationship, Animals, Tetrazole, Amino Acids, Molecular Biology, chemistry.chemical_classification, Organic Chemistry, Amino acid, Rats, chemistry, Molecular Medicine, Receptors, Progesterone
Abstract

Two classes of amino acid-derived heterocyclic progesterone receptor ligands were developed to address the metabolic issues posed by the dimethyl amide functionality of the lead compound (1). The tetrazole-derived ligands behaved as potent partial agonists, while the 1,2,4-triazole ligands behaved as potent full agonists.

Published
2009

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