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Start Over Author "Laping NJ" Journal bioorganic medicinal chemistry letters
4 results on '"Laping NJ"'

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

Author

Kallander LS, Washburn DG, Hoang TH, Frazee JS, Stoy P, Johnson L, Lu Q, Hammond M, Barton LS, Patterson JR, Azzarano LM, Nagilla R, Madauss KP, Williams SP, Stewart EL, Duraiswami C, Grygielko ET, Xu X, Laping NJ, Bray JD, and Thompson SK

Subjects
Animals, Binding Sites, Carbamates chemistry, Crystallography, X-Ray, ERG1 Potassium Channel, Endometriosis drug therapy, Ether-A-Go-Go Potassium Channels metabolism, Female, Humans, Pyrrolidines chemical synthesis, Pyrrolidines pharmacokinetics, Rats, Receptors, Progesterone metabolism, Sulfonamides chemistry, Pyrrolidines chemistry, Receptors, Progesterone agonists
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., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Published
2010
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2. Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists.

Author

Thompson SK, Washburn DG, Frazee JS, Madauss KP, Hoang TH, Lapinski L, Grygielko ET, Glace LE, Trizna W, Williams SP, Duraiswami C, Bray JD, and Laping NJ

Subjects
Administration, Oral, Animals, Binding Sites, Computer Simulation, Crystallography, X-Ray, Drug Design, Models, Animal, Protein Structure, Tertiary, Pyrrolidines administration & dosage, Pyrrolidines chemical synthesis, Rats, Receptors, Progesterone metabolism, Pyrrolidines chemistry, Receptors, Progesterone agonists
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
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3. Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors.

Author

Hammond M, Washburn DG, Hoang HT, Manns S, Frazee JS, Nakamura H, Patterson JR, Trizna W, Wu C, Azzarano LM, Nagilla R, Nord M, Trejo R, Head MS, Zhao B, Smallwood AM, Hightower K, Laping NJ, Schnackenberg CG, and Thompson SK

Subjects
Administration, Oral, Animals, Biological Availability, Drug Design, Glucocorticoids chemistry, Glucuronic Acid chemistry, Immediate-Early Proteins chemistry, Inhibitory Concentration 50, Models, Chemical, Molecular Conformation, Protein Kinase Inhibitors antagonists & inhibitors, Protein Serine-Threonine Kinases chemistry, Rats, Structure-Activity Relationship, Chemistry, Pharmaceutical methods, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Immediate-Early Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors
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
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4. Synthesis and SAR of amino acid-derived heterocyclic progesterone receptor full and partial agonists.

Author

Hammond M, Patterson JR, Manns S, Hoang TH, Washburn DG, Trizna W, Glace L, Grygielko ET, Nagilla R, Nord M, Fries HE, Minick DJ, Laping NJ, Bray JD, and Thompson SK

Subjects
Amino Acids chemistry, Animals, Rats, Receptors, Progesterone metabolism, Structure-Activity Relationship, Tetrazoles chemistry, Tetrazoles pharmacokinetics, Receptors, Progesterone agonists, Tetrazoles chemical synthesis
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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