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Your search keyword '"Eidenschenk C"' showing total 4 results
Start Over Author "Eidenschenk C" Topic sulfonamides
4 results on '"Eidenschenk C"'

1. Discovery of 1-{4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORγ) inverse agonist.

Author

Fauber BP, René O, Deng Y, DeVoss J, Eidenschenk C, Everett C, Ganguli A, Gobbi A, Hawkins J, Johnson AR, La H, Lesch J, Lockey P, Norman M, Ouyang W, Summerhill S, and Wong H

Subjects
Administration, Oral, Animals, Biological Availability, Dose-Response Relationship, Drug, Female, Humans, Leukocytes, Mononuclear cytology, Mice, Mice, Inbred C57BL, Models, Molecular, Molecular Dynamics Simulation, Molecular Structure, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Protein Binding, Protein Conformation, Rats, Structure-Activity Relationship, Cyclic S-Oxides administration & dosage, Cyclic S-Oxides pharmacology, Drug Discovery, Drug Inverse Agonism, Leukocytes, Mononuclear drug effects, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Sulfonamides chemistry, Thiazines administration & dosage, Thiazines pharmacology
Abstract

Retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide 1 as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly selective RORc inverse agonist profile. The most advanced δ-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PK/PD model support the evaluation of 27 in preclinical studies.

Published
2015
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2. A reversed sulfonamide series of selective RORc inverse agonists.

Author

van Niel MB, Fauber BP, Cartwright M, Gaines S, Killen JC, René O, Ward SI, de Leon Boenig G, Deng Y, Eidenschenk C, Everett C, Gancia E, Ganguli A, Gobbi A, Hawkins J, Johnson AR, Kiefer JR, La H, Lockey P, Norman M, Ouyang W, Qin A, Wakes N, Waszkowycz B, and Wong H

Subjects
Binding Sites, Cell Survival drug effects, Crystallography, X-Ray, Cytokines biosynthesis, Drug Inverse Agonism, HEK293 Cells, Humans, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear drug effects, Molecular Dynamics Simulation, Nuclear Receptor Subfamily 1, Group F, Member 3 antagonists & inhibitors, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Protein Binding, Protein Structure, Tertiary, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides toxicity, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Sulfonamides chemistry
Abstract

The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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3. Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists.

Author

Fauber BP, René O, de Leon Boenig G, Burton B, Deng Y, Eidenschenk C, Everett C, Gobbi A, Hymowitz SG, Johnson AR, La H, Liimatta M, Lockey P, Norman M, Ouyang W, Wang W, and Wong H

Subjects
Animals, Binding Sites drug effects, Blood Proteins metabolism, Crystallography, X-Ray, Dogs, Dose-Response Relationship, Drug, Drug Design, Humans, Hydrophobic and Hydrophilic Interactions, Madin Darby Canine Kidney Cells, Models, Molecular, Molecular Structure, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Rats, Solubility, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Blood Proteins chemistry, Cell Membrane Permeability drug effects, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Sulfonamides pharmacology
Abstract

Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma-protein unbound fraction and improvements in cellular permeability and aqueous solubility., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Published
2014
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4. Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc.

Author

Fauber BP, de Leon Boenig G, Burton B, Eidenschenk C, Everett C, Gobbi A, Hymowitz SG, Johnson AR, Liimatta M, Lockey P, Norman M, Ouyang W, René O, and Wong H

Subjects
Binding Sites, Crystallography, X-Ray, Drug Inverse Agonism, Humans, Hydrocarbons, Fluorinated chemical synthesis, Hydrocarbons, Fluorinated chemistry, Hydrocarbons, Fluorinated metabolism, Interferon-gamma metabolism, Interleukin-17 metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Molecular Dynamics Simulation, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Protein Binding drug effects, Protein Structure, Tertiary, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides metabolism, Drug Design, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Propanols chemistry, Sulfonamides chemistry, Sulfonamides pharmacology
Abstract

The structure-activity relationships of T0901317 analogs were explored as RORc inverse agonists using the principles of property- and structure-based drug design. An X-ray co-crystal structure of T0901317 and RORc was obtained and provided molecular insight into why T0901317 functioned as an inverse agonist of RORc; whereas, the same ligand functioned as an agonist of FXR, LXR, and PXR. The structural data was also used to design inhibitors with improved RORc biochemical and cellular activities. The improved inhibitors possessed enhanced selectivity profiles (rationalized using the X-ray crystallographic data) against other nuclear receptors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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