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Your search keyword '"Scott K. Thompson"' showing total 6 results
Start Over Author "Scott K. Thompson" Journal bioorganicmedicinal chemistry letters
6 results on '"Scott K. Thompson"'

1. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

Author

Eugene T. Grygielko, Patrick Stoy, Eugene L. Stewart, Tram H. Hoang, Johnson Latisha C, Jaclyn R. Patterson, Marlys Hammond, Qing Lu, Linda S. Barton, Rakesh Nagilla, David G. Washburn, Shawn P. Williams, Lara S. Kallander, Jeffrey D. Bray, Leonard M. Azzarano, Scott K. Thompson, Chaya Duraiswami, James S. Frazee, Kevin P. Madauss, Nicholas J. Laping, and Xiaoping Xu

Subjects
ERG1 Potassium Channel, Pyrrolidines, medicine.drug_class, Stereochemistry, Clinical Biochemistry, hERG, Endometriosis, Pharmaceutical Science, Carboxamide, Crystallography, X-Ray, Biochemistry, Chemical synthesis, Partial agonist, Pyrrolidine, chemistry.chemical_compound, In vivo, Drug Discovery, Progesterone receptor, medicine, Animals, Humans, Receptor, Molecular Biology, Sulfonamides, Binding Sites, biology, Chemistry, Organic Chemistry, Ether-A-Go-Go Potassium Channels, Rats, biology.protein, Molecular Medicine, Female, Carbamates, Receptors, Progesterone
Abstract

The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

Published
2009

2. 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

3. 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

4. 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

5. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

Author

Derek J. Parks, Angela Smallwood, Nino Campobasso, David G. Washburn, Melanie Nord, Tram H. Hoang, Michael Jaye, Scott K. Thompson, Christopher P. Evans, Christine L. Webb, Chaya Duraiswami, and Kelly A. Frank

Subjects
Agonist, Indoles, Tertiary amine, Stereochemistry, medicine.drug_class, Clinical Biochemistry, Molecular Conformation, Pharmaceutical Science, Administration, Oral, Receptors, Cytoplasmic and Nuclear, Crystallography, X-Ray, digestive system, Biochemistry, Mice, Structure-Activity Relationship, Drug Discovery, polycyclic compounds, medicine, Animals, Combinatorial Chemistry Techniques, Liver X receptor, Molecular Biology, Liver X Receptors, Indole test, Molecular Structure, Chemistry, Pulmonary inflammation, Macrophages, Organic Chemistry, food and beverages, Orphan Nuclear Receptors, Rats, DNA-Binding Proteins, Cholesterol, Nuclear receptor, Molecular Medicine, lipids (amino acids, peptides, and proteins), Pharmacophore
Abstract

A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXRα will be disclosed.

Published
2008

6. Design and synthesis of diaminopyrrolidinone inhibitors of human osteoclast cathepsin K

Author

Richard M. Keenan, Daniel F. Veber, Kevin J. Duffy, Scott K. Thompson, Lance Ridgers, Renee L. DesJarlais, Thaddeus A. Tomaszek, and Mary J. Bossard

Subjects
Models, Molecular, Stereochemistry, Clinical Biochemistry, Cathepsin K, Pharmaceutical Science, Osteoclasts, Peptide, Cysteine Proteinase Inhibitors, Cleavage (embryo), Crystallography, X-Ray, Biochemistry, Chemical synthesis, Structure-Activity Relationship, Cathepsin O, Osteoclast, Drug Discovery, medicine, Humans, Amines, Molecular Biology, chemistry.chemical_classification, biology, Organic Chemistry, Cathepsins, Pyrrolidinones, medicine.anatomical_structure, Enzyme, chemistry, Enzyme inhibitor, Drug Design, biology.protein, Molecular Medicine, Peptides
Abstract

The structure-based design and synthesis of lactam-constrained azapeptide inhibitors of human cathepsin K are described. Enhanced stability to proteolytic cleavage over acyclic analogues is discussed.

Published
1999

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