LLY-2707, A Novel Nonsteroidal Glucocorticoid Antagonist That Reduces Atypical Antipsychotic–Associated Weight Gain in Rats
| Autor: | Anne B. Need, Jesline T. Alexander-Chacko, Donald R. Gehlert, Dana Sindelar, Janice Shaw, Matthew W. Carson, Robert J. Barr, Michael J. Coghlan, Michelle Morin |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Olanzapine medicine.medical_specialty Indoles medicine.drug_class Atypical antipsychotic CHO Cells Pharmacology Weight Gain Heterocyclic Compounds 4 or More Rings Rats Sprague-Dawley Mice Random Allocation chemistry.chemical_compound Cricetulus Receptors Glucocorticoid Cell Line Tumor Cricetinae Internal medicine Dopamine receptor D2 Weight Loss medicine Animals Humans Aza Compounds Sulfonamides business.industry Antiglucocorticoid Antagonist Mifepristone Rats Mice Inbred C57BL HEK293 Cells Endocrinology chemistry Molecular Medicine Female medicine.symptom business Weight gain Glucocorticoid Antipsychotic Agents medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 348:192-201 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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 [(3)H]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. |
| Databáze: | OpenAIRE |
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