title: Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139, USA. greg.bebernitz@novartis.com
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Bebernitz
authors.forename: Valerie
authors.initials: V
authors.lastname: Beaulieu
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Dale
authors.forename: Richard
authors.initials: R
authors.lastname: Deacon
authors.forename: Alokesh
authors.initials: A
authors.lastname: Duttaroy
authors.forename: Jiaping
authors.initials: J
authors.lastname: Gao
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Grondine
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
authors.forename: Mesut
authors.initials: M
authors.lastname: Kakmak
authors.forename: Michael
authors.initials: M
authors.lastname: Kavana
authors.forename: Louise C
authors.initials: LC
authors.lastname: Kirman
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Liang
authors.forename: Wieslawa M
authors.initials: WM
authors.lastname: Maniara
authors.forename: Siralee
authors.initials: S
authors.lastname: Munshi
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Nadkarni
authors.forename: Herbert F
authors.initials: HF
authors.lastname: Schuster
authors.forename: Travis
authors.initials: T
authors.lastname: Stams
authors.forename: Irene
authors.initials: I
authors.lastname: St Denny
authors.forename: Paul M
authors.initials: PM
authors.lastname: Taslimi
authors.forename: Brian
authors.initials: B
authors.lastname: Vash
authors.forename: Shari L
authors.initials: SL
authors.lastname: Caplan
mesh_terms: 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
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013449:Sulfonamides; D005941:Glucokinase