title: Design and optimization of pyrazinecarboxamide-based inhibitors of diacylglycerol acyltransferase 1 (DGAT1) leading to a clinical candidate dimethylpyrazinecarboxamide phenylcyclohexylacetic acid (AZD7687).
abstract: A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.
authors.affiliation: Cardiovascular and Gastrointestinal Innovative Medicines Unit Mölndal, AstraZeneca R&D, S-431 83 Mölndal, Sweden.
authors.forename: Jonas G
authors.initials: JG
authors.lastname: Barlind
authors.forename: Udo A
authors.initials: UA
authors.lastname: Bauer
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: Robert D M
authors.initials: RD
authors.lastname: Davies
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
authors.forename: Clare D
authors.initials: CD
authors.lastname: Hammond
authors.forename: Ragnar
authors.initials: R
authors.lastname: Hovland
authors.forename: Petra
authors.initials: P
authors.lastname: Johannesson
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Johansson
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kemmitt
authors.forename: Bo T
authors.initials: BT
authors.lastname: Lindmark
authors.forename: Pablo
authors.initials: P
authors.lastname: Morentin Gutierrez
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Noeske
authors.forename: Andreas
authors.initials: A
authors.lastname: Nordin
authors.forename: Charles J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Annika U
authors.initials: AU
authors.lastname: Petersson
authors.forename: Alma
authors.initials: A
authors.lastname: Redzic
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Turnbull
authors.forename: Johanna
authors.initials: J
authors.lastname: Vinblad
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011719:Pyrazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility
chemical_list: D000085:Acetates; D004791:Enzyme Inhibitors; D011719:Pyrazines; C578442:AZD7687; C494881:DGAT1 protein, human; D051048:Diacylglycerol O-Acyltransferase