SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides: discovery of PSN-GK1.
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.
Bertram
Lisa S
LS
OSI) Prosidion, Windrush Court, Watlington Road, Oxford OX4 6LT, United Kingdom.
Black
Daniel
D
Briner
Paul H
PH
Chatfield
Rosemary
R
Cooke
Andrew
A
Fyfe
Matthew C T
MC
Murray
P John
PJ
Naud
Frédéric
F
Nawano
Masao
M
Procter
Martin J
MJ
Rakipovski
Günaj
G
Rasamison
Chrystelle M
CM
Reynet
Christine
C
Schofield
Karen L
KL
Shah
Vilas K
VK
Spindler
Felix
F
Taylor
Amanda
A
Turton
Roy
R
Williams
Geoffrey M
GM
Wong-Kai-In
Philippe
P
Yasuda
Kosuke
K
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*
C523511:2-(4-cyclopropanesulfonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide; D007004:Hypoglycemic Agents; D013450:Sulfones; D013844:Thiazoles; D005941:Glucokinase