title: Optimisation of pharmacokinetic properties in a neutral series of 11β-HSD1 inhibitors.
abstract: 11β-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11β-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.
authors.affiliation: Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. jamie.scott@astrazeneca.com
authors.forename: James S
authors.initials: JS
authors.lastname: Scott
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Gill
authors.forename: Linda
authors.initials: L
authors.lastname: Godfrey
authors.forename: Sam D
authors.initials: SD
authors.lastname: Groombridge
authors.forename: Amanda
authors.initials: A
authors.lastname: Rees
authors.forename: John
authors.initials: J
authors.lastname: Revill
authors.forename: Paul
authors.initials: P
authors.lastname: Schofield
authors.forename: Pernilla
authors.initials: P
authors.lastname: Sörme
authors.forename: Andrew
authors.initials: A
authors.lastname: Stocker
authors.forename: John G
authors.initials: JG
authors.lastname: Swales
authors.forename: Paul R O
authors.initials: PR
authors.lastname: Whittamore
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D013438:Sulfhydryl Compounds; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1