title: Pharmacological characterization of the selective 11β-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes.
abstract: To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11β-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11β-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 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, Birkendorfer Straße 67, 88397 Biberach an der Riß, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Himmelsbach
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 67, 88397 Biberach an der Riß, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Nar
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 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: Joan
authors.initials: J
authors.lastname: Guo
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Shi
authors.initials: S
authors.lastname: Meng
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
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: Linghang
authors.initials: L
authors.lastname: Zhuang
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* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
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; Inhibitor; Liver; Type 2 diabetes