title: Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes.
abstract: A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
authors.affiliation: Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. william.mccoull@astrazeneca.com
authors.forename: William
authors.initials: W
authors.lastname: McCoull
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Addie
authors.forename: Alan M
authors.initials: AM
authors.lastname: Birch
authors.forename: Susan
authors.initials: S
authors.lastname: Birtles
authors.forename: Linda K
authors.initials: LK
authors.lastname: Buckett
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Butlin
authors.forename: Suzanne S
authors.initials: SS
authors.lastname: Bowker
authors.forename: Scott
authors.initials: S
authors.lastname: Boyd
authors.forename: Stephen
authors.initials: S
authors.lastname: Chapman
authors.forename: Robert D M
authors.initials: RD
authors.lastname: Davies
authors.forename: Craig S
authors.initials: CS
authors.lastname: Donald
authors.forename: Clive P
authors.initials: CP
authors.lastname: Green
authors.forename: Chloe
authors.initials: C
authors.lastname: Jenner
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kemmitt
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Moody
authors.forename: Pablo Morentin
authors.initials: PM
authors.lastname: Gutierrez
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Newcombe
authors.forename: Thorsten
authors.initials: T
authors.lastname: Nowak
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Packer
authors.forename: Alleyn T
authors.initials: AT
authors.lastname: Plowright
authors.forename: John
authors.initials: J
authors.lastname: Revill
authors.forename: Paul
authors.initials: P
authors.lastname: Schofield
authors.forename: Chris
authors.initials: C
authors.lastname: Sheldon
authors.forename: Steve
authors.initials: S
authors.lastname: Stokes
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Turnbull
authors.forename: Steven J Y
authors.initials: SJ
authors.lastname: Wang
authors.forename: David P
authors.initials: DP
authors.lastname: Whalley
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Wood
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D057166:High-Throughput Screening Assays; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
chemical_list: C575053:AZD3988; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D008024:Ligands; D010069:Oxadiazoles; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase