Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.
Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.
Bebernitz
Gregory R
GR
Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139, USA. greg.bebernitz@novartis.com
Beaulieu
Valerie
V
Dale
Bethany A
BA
Deacon
Richard
R
Duttaroy
Alokesh
A
Gao
Jiaping
J
Grondine
Melissa S
MS
Gupta
Ramesh C
RC
Kakmak
Mesut
M
Kavana
Michael
M
Kirman
Louise C
LC
Liang
Jinsheng
J
Maniara
Wieslawa M
WM
Munshi
Siralee
S
Nadkarni
Sunil S
SS
Schuster
Herbert F
HF
Stams
Travis
T
St Denny
Irene
I
Taslimi
Paul M
PM
Vash
Brian
B
Caplan
Shari L
SL
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005941:Glucokinase / Q000187:drug effects*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013449:Sulfonamides; D005941:Glucokinase