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Research ArticleDrug Discovery and Translational Medicine

LLY-2707, A Novel Nonsteroidal Glucocorticoid Antagonist That Reduces Atypical Antipsychotic–Associated Weight Gain in Rats

Dana K. Sindelar, Mathew W. Carson, Michelle Morin, Janice Shaw, Robert J. Barr, Anne Need, Jesline Alexander-Chacko, Michael Coghlan and Donald R. Gehlert
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 192-201; DOI: https://doi.org/10.1124/jpet.113.205864
Dana K. Sindelar
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Mathew W. Carson
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Michelle Morin
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Janice Shaw
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Robert J. Barr
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Anne Need
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Jesline Alexander-Chacko
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Michael Coghlan
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Donald R. Gehlert
Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
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Abstract

Weight gain and diabetes have been reported during treatment with atypical antipsychotic drugs (AAPDs). Patients treated with the glucocorticoid receptor antagonist (GRA) and the progesterone receptor antagonist (PRA) mifepristone [estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-(11β,17β)-(9CI)] experienced significant reduction in the weight gain observed when patients were treated with olanzapine or risperidone. To understand the pharmacology responsible for this finding, we discovered LLY-2707 [N-(5-(tert-butyl)-3-(2-fluoro-5-methylpyridin-4-yl)-2-methyl-1H-indol-7-yl)methanesulfonamide], a novel and selective GRA, and evaluated its utility in preclinical models of AAPD-associated weight gain and diabetes. In vitro, LLY-2707 was a highly selective and potent GRA. GR occupancy in vivo was assessed using ex vivo binding where LLY-2707 inhibited [3H]dexamethasone binding to the liver. Modest but statistically significant decreases in brain ex vivo binding were observed with high doses of CORT-108297 [(R)-4α-(ethoxymethyl)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline] and LLY-2707, but mifepristone inhibited at all doses. Central activity of the GRAs was confirmed by their ability to suppress amphetamine-induced increases in locomotor activity. The increases in the body weight of female rats treated with olanzapine (2 mg/kg PO) over 14 days were reduced in a dose-dependent manner by coadministration of LLY-2707. Similar decreases, although less robust, in body weight were seen with mifepristone and CORT-108297. In addition, sGRAs prevented the glucose excursion after intragastric olanzapine infusions consistent with a direct effect on the hyperglycemia observed during treatment with AAPDs. At doses effectively preventing weight gain, LLY-2707 did not substantially interfere with the dopamine D2 receptor occupancy by olanzapine. Therefore, GRA coadministration may provide a novel treatment modality to prevent the weight gain and diabetes observed during treatment with AAPDs.

Footnotes

  • dx.doi.org/10.1124/jpet.113.205864.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleDrug Discovery and Translational Medicine

Glucocorticoid Receptor Antagonism and the HPAA

Dana K. Sindelar, Mathew W. Carson, Michelle Morin, Janice Shaw, Robert J. Barr, Anne Need, Jesline Alexander-Chacko, Michael Coghlan and Donald R. Gehlert
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 192-201; DOI: https://doi.org/10.1124/jpet.113.205864

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Research ArticleDrug Discovery and Translational Medicine

Glucocorticoid Receptor Antagonism and the HPAA

Dana K. Sindelar, Mathew W. Carson, Michelle Morin, Janice Shaw, Robert J. Barr, Anne Need, Jesline Alexander-Chacko, Michael Coghlan and Donald R. Gehlert
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 192-201; DOI: https://doi.org/10.1124/jpet.113.205864
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