title: Identification and design of a novel series of MGAT2 inhibitors.
abstract: [Acyl CoA]monoacylglycerol acyltransferase 2 (MGAT2) is of interest as a target for therapeutic treatment of diabetes, obesity and other diseases which together constitute the metabolic syndrome. In this Letter we report our discovery and optimisation of a novel series of MGAT2 inhibitors. The development of the SAR of the series and a detailed discussion around some key parameters monitored and addressed during the lead generation phase will be given. The in vivo results from an oral lipid tolerance test (OLTT) using the MGAT2 inhibitor (S)-10, shows a significant reduction (68% inhibition relative to naїve, p<0.01) in plasma triacylglycerol (TAG) concentration.
authors.affiliation: AstraZeneca R&D, Cardiovascular & Gastrointestinal Innovative Medicines Unit Mölndal, SE-431 83 Mölndal, Sweden.
authors.forename: Jonas G
authors.initials: JG
authors.lastname: Barlind
authors.forename: Linda K
authors.initials: LK
authors.lastname: Buckett
authors.forename: Sharon G
authors.initials: SG
authors.lastname: Crosby
authors.forename: Öjvind
authors.initials: Ö
authors.lastname: Davidsson
authors.forename: Hans
authors.initials: H
authors.lastname: Emtenäs
authors.forename: Anne
authors.initials: A
authors.lastname: Ertan
authors.forename: Ulrik
authors.initials: U
authors.lastname: Jurva
authors.forename: Malin
authors.initials: M
authors.lastname: Lemurell
authors.forename: Pablo Morentin
authors.initials: PM
authors.lastname: Gutierrez
authors.forename: Karolina
authors.initials: K
authors.lastname: Nilsson
authors.forename: Gavin
authors.initials: G
authors.lastname: O'Mahony
authors.forename: Annika U
authors.initials: AU
authors.lastname: Petersson
authors.forename: Alma
authors.initials: A
authors.lastname: Redzic
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wågberg
authors.forename: Zhong-Qing
authors.initials: ZQ
authors.lastname: Yuan
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D051379:Mice; D049329:Nanostructures / Q000737:chemistry; D011205:Povidone / Q000737:chemistry; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D014280:Triglycerides; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase; D011205:Povidone