title: Design, synthesis and SAR of novel glucokinase activators.
abstract: Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes.
authors: Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA.
authors: Zacharia S
authors: ZS
authors: Cheruvallath
authors: Stephen L
authors: SL
authors: Gwaltney
authors: Mark
authors: M
authors: Sabat
authors: Mingnam
authors: M
authors: Tang
authors: Jun
authors: J
authors: Feng
authors: Haixia
authors: H
authors: Wang
authors: Joanne
authors: J
authors: Miura
authors: Prasuna
authors: P
authors: Guntupalli
authors: Andy
authors: A
authors: Jennings
authors: David
authors: D
authors: Hosfield
authors: Bumsup
authors: B
authors: Lee
authors: Yiqin
authors: Y
authors: Wu
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology*; D004195:Disease Models, Animal; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D011728:Pyridones; D005941:Glucokinase