title: SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides: discovery of PSN-GK1.
abstract: Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.
authors.affiliation: OSI) Prosidion, Windrush Court, Watlington Road, Oxford OX4 6LT, United Kingdom.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Bertram
authors.forename: Daniel
authors.initials: D
authors.lastname: Black
authors.forename: Paul H
authors.initials: PH
authors.lastname: Briner
authors.forename: Rosemary
authors.initials: R
authors.lastname: Chatfield
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.forename: Matthew C T
authors.initials: MC
authors.lastname: Fyfe
authors.forename: P John
authors.initials: PJ
authors.lastname: Murray
authors.forename: Frédéric
authors.initials: F
authors.lastname: Naud
authors.forename: Masao
authors.initials: M
authors.lastname: Nawano
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Procter
authors.forename: Günaj
authors.initials: G
authors.lastname: Rakipovski
authors.forename: Chrystelle M
authors.initials: CM
authors.lastname: Rasamison
authors.forename: Christine
authors.initials: C
authors.lastname: Reynet
authors.forename: Karen L
authors.initials: KL
authors.lastname: Schofield
authors.forename: Vilas K
authors.initials: VK
authors.lastname: Shah
authors.forename: Felix
authors.initials: F
authors.lastname: Spindler
authors.forename: Amanda
authors.initials: A
authors.lastname: Taylor
authors.forename: Roy
authors.initials: R
authors.lastname: Turton
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Williams
authors.forename: Philippe
authors.initials: P
authors.lastname: Wong-Kai-In
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yasuda
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D005260:Female; D005941:Glucokinase / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013844:Thiazoles / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C523511:2-(4-cyclopropanesulfonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide; D007004:Hypoglycemic Agents; D013450:Sulfones; D013844:Thiazoles; D005941:Glucokinase