title: Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors.
abstract: Through high throughput screening and subsequent hit identification and optimization, we synthesized a series of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as the first reported potent and reversible GFAT inhibitors. SAR studies of this class of compounds indicated significant impact on GFAT inhibition potency by substitutions on the A-ring and C-ring. The ketone group was found to be necessary for high potency. Compound 28 (RO0509347) demonstrated potent GFAT inhibition (IC(50)=1μM) with a desirable pharmacokinetic profile in rats, and showed significant efficacy in reducing the glucose excursion in an OGTT test in ob/ob mice.
authors.affiliation: Department of Discovery Chemistry and Metabolic Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States. yimin.qian@roche.com
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmad
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.forename: Nam
authors.initials: N
authors.lastname: Le
authors.forename: Frank
authors.initials: F
authors.lastname: Mennona
authors.forename: Steven
authors.initials: S
authors.lastname: Mischke
authors.forename: Sung-Sau
authors.initials: SS
authors.lastname: So
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Charles
authors.initials: C
authors.lastname: Burghardt
authors.forename: Shahid
authors.initials: S
authors.lastname: Tannu
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.forename: Jarema
authors.initials: J
authors.lastname: Kochan
authors.forename: David
authors.initials: D
authors.lastname: Bolin
mesh_terms: D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)