title: Discovery, structure-activity relationships, pharmacokinetics, and efficacy of glucokinase activator (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675).
abstract: 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.
authors.affiliation: Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey 07110, USA.
authors.forename: Nancy-Ellen
authors.initials: NE
authors.lastname: Haynes
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Corbett
authors.forename: Fred T
authors.initials: FT
authors.lastname: Bizzarro
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Guertin
authors.forename: Darryl W
authors.initials: DW
authors.lastname: Hilliard
authors.forename: George W
authors.initials: GW
authors.lastname: Holland
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kester
authors.forename: Paige E
authors.initials: PE
authors.lastname: Mahaney
authors.forename: Lida
authors.initials: L
authors.lastname: Qi
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Spence
authors.forename: John
authors.initials: J
authors.lastname: Tengi
authors.forename: Mark T
authors.initials: MT
authors.lastname: Dvorozniak
authors.forename: Aruna
authors.initials: A
authors.lastname: Railkar
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grippo
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.forename: Ramakanth
authors.initials: R
authors.lastname: Sarabu
mesh_terms: 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
chemical_list: 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