title: Influence of sub-chronic selective 11β-hydroxysteroid dehydrogenase 1 inhibition on the hypothalamic-pituitary-adrenal axis in female cynomolgus monkeys.
abstract: Inhibition of local cortisol regeneration from circulating cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. Chronic modulation of glucocorticoid homeostasis may result in hypothalamic-pituitary-adrenal (HPA) axis stimulation. HPA axis over-activation leading androgen excess would be undesirable in a therapeutic intervention designed to treat a chronic condition such as the metabolic syndrome. To address whether 11β-HSD1 inhibition would lead to excess androgens, we treated female cynomolgus monkeys with a selective inhibitor, BI 135558, for 4 weeks. Continual action of the compound over the dosing period was confirmed by constant plasma exposure, and a maintained change in urinary glucocorticoid metabolites consistent with 11β-HSD1 inhibition. No significant changes in adrenal function, as evidenced by an adrenocorticotropic hormone (ATCH) challenge, were observed. An examination of androgenic hormones revealed a slight increase in dehydroepiandrosterone sulfate (DHEA-S), while other hormones such as testosterone remained within reference values. Overall, treatment with BI 135558 in monkeys did not result in obvious over-activation of the HPA axis.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstraße 67, 88397 Biberach an der Riß, Germany. Electronic address: bradford.hamilton@boehringer-ingelheim.com.
authors.forename: Bradford S
authors.initials: BS
authors.lastname: Hamilton
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstraße 67, 88397 Biberach an der Riß, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Schoelch
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstraße 67, 88397 Biberach an der Riß, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schuler-Metz
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Paula
authors.initials: P
authors.lastname: Krosky
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Deepak S
authors.initials: DS
authors.lastname: Lala
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Claremon
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Gerard M
authors.initials: GM
authors.lastname: McGeehan
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000502:physiology; D008252:Macaca fascicularis; D010078:Oxazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000502:physiology; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C000600796:6-(2-hydroxy-2-methylpropyl)-3-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one; D004791:Enzyme Inhibitors; D010078:Oxazines; D011728:Pyridones; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
keywords: 11β-hydroxysteroid dehydrogenase 1; Adipose tissue; HPA; Inhibitor; Liver