Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675).
Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.
Haynes
Nancy-Ellen
NE
Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey 07110, USA.
Corbett
Wendy L
WL
Bizzarro
Fred T
FT
Guertin
Kevin R
KR
Hilliard
Darryl W
DW
Holland
George W
GW
Kester
Robert F
RF
Mahaney
Paige E
PE
Qi
Lida
L
Spence
Cheryl L
CL
Tengi
John
J
Dvorozniak
Mark T
MT
Railkar
Aruna
A
Matschinsky
Franz M
FM
Grippo
Joseph F
JF
Grimsby
Joseph
J
Sarabu
Ramakanth
R
D000818:Animals; D001786:Blood Glucose; D002460:Cell Line; D003603:Cytotoxins; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005941:Glucokinase / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007328:Insulin; D008297:Male; D051379:Mice; D010599:Pharmacokinetics; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
C549923:3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide; D001786:Blood Glucose; D003603:Cytotoxins; D007004:Hypoglycemic Agents; D007328:Insulin; D013450:Sulfones; D013844:Thiazoles; D005941:Glucokinase