title: LLY-2707, a novel nonsteroidal glucocorticoid antagonist that reduces atypical antipsychotic-associated weight gain in rats.
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 [(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.
authors.affiliation: Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Dana K
authors.initials: DK
authors.lastname: Sindelar
authors.forename: Mathew W
authors.initials: MW
authors.lastname: Carson
authors.forename: Michelle
authors.initials: M
authors.lastname: Morin
authors.forename: Janice
authors.initials: J
authors.lastname: Shaw
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Barr
authors.forename: Anne
authors.initials: A
authors.lastname: Need
authors.forename: Jesline
authors.initials: J
authors.lastname: Alexander-Chacko
authors.forename: Michael
authors.initials: M
authors.lastname: Coghlan
authors.forename: Donald R
authors.initials: DR
authors.lastname: Gehlert
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D057809:HEK293 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000737:chemistry / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000502:physiology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects* / Q000502:physiology; D015431:Weight Loss / Q000187:drug effects* / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D001372:Aza Compounds; C558517:CORT 108297; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; C586215:N-(5-(tert-butyl)-3-(2-fluoro-5-methylpyridin-4-yl)-2-methyl-1H-indol-7-yl)methanesulfonamide; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D015735:Mifepristone