title: Free-Wilson and structural approaches to co-optimizing human and rodent isoform potency for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors.
abstract: 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) has been a target of intensive research efforts across the pharmaceutical industry, due to its potential for the treatment of type II diabetes and other elements of the metabolic syndrome. To demonstrate the value of 11β-HSD1 in preclinical models, we required inhibitors with good potency against both human and rodent isoforms. Herein, we describe our efforts to understand how to co-optimize human and murine potency within the (5-hydroxy-2-adamantyl)-pyrimidine-5-carboxamide series. Two approaches are described-a data-driven (Free-Wilson) analysis and a structure-based design approach. The conclusions from these approaches were used to inform an efficient campaign to design compounds with consistently good human/murine potency within a logD(7.4) range of 1-3. Compounds 20 and 26 demonstrated good rodent PK, which allowed us to demonstrate a PK/PD relationship in rat and mouse. We then evaluated 26 against glycemic and body weight end points in murine disease models, where it demonstrated glucose and body weight efficacy at 300 mg/kg/day but only body weight efficacy at 50 mg/kg/day, despite providing >90% target engagement in the liver.
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG, United Kingdom. frederick.goldberg@astrazeneca.com
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Goldberg
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
authors.forename: James S
authors.initials: JS
authors.lastname: Scott
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Snelson
authors.forename: Sam D
authors.initials: SD
authors.lastname: Groombridge
authors.forename: Craig S
authors.initials: CS
authors.lastname: Donald
authors.forename: Stuart N L
authors.initials: SN
authors.lastname: Bennett
authors.forename: Cristian
authors.initials: C
authors.lastname: Bodin
authors.forename: Pablo Morentin
authors.initials: PM
authors.lastname: Gutierrez
authors.forename: Amy C
authors.initials: AC
authors.lastname: Gyte
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1