title: C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.
abstract: Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Du
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hinklin
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Dransfield
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jaehyeon
authors.initials: J
authors.lastname: Park
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Kohn
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Vatee
authors.initials: V
authors.lastname: Pattaropong
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: SuJen
authors.initials: S
authors.lastname: Lai
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Zice
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Xianyun
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: David
authors.initials: D
authors.lastname: Chow
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Davda
authors.affiliation: Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Veniant
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Anderson
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Baer
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Josef R
authors.initials: JR
authors.lastname: Bencsik
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Boyd
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Mark Joseph
authors.initials: MJ
authors.lastname: Chicarelli
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohr
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Condroski
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Walter E
authors.initials: WE
authors.lastname: DeWolf
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Marion
authors.initials: M
authors.lastname: Conn
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Thanhvien
authors.initials: T
authors.lastname: Tran
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Yang
authors.affiliation: Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Aicher
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Coward
authors.affiliation: Amgen, Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Houze
keywords: GKA; Type 2 diabetes; glucokinase activator; methyl urea-substituted pyridines