title: Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif.
abstract: Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases Chemistry, Pfizer Worldwide Research and Development, 620 Memorial Dr, Cambridge, MA 02139, USA. kevin.filipski@pfizer.com
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Jianwei
authors.initials: J
authors.lastname: Bian
authors.forename: Christian
authors.initials: C
authors.lastname: Perreault
authors.forename: Gary E
authors.initials: GE
authors.lastname: Aspnes
authors.forename: Mary T
authors.initials: MT
authors.lastname: Didiuk
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dow
authors.forename: Richard F
authors.initials: RF
authors.lastname: Hank
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Maguire
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Zeng
authors.forename: Shenping
authors.initials: S
authors.lastname: Liu
authors.forename: John D
authors.initials: JD
authors.lastname: Knafels
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.forename: David R
authors.initials: DR
authors.lastname: Derksen
authors.forename: Francis
authors.initials: F
authors.lastname: Bourbonais
authors.forename: Ketan S
authors.initials: KS
authors.lastname: Gajiwala
authors.forename: Michael
authors.initials: M
authors.lastname: Hickey
authors.forename: Theodore O
authors.initials: TO
authors.lastname: Johnson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Humphries
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
mesh_terms: D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D020536:Enzyme Activators / Q000737:chemistry*; D005941:Glucokinase / Q000378:metabolism*; D008958:Models, Molecular; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats
chemical_list: D020536:Enzyme Activators; D011744:Pyrimidinones; D005941:Glucokinase
keywords: Glucokinase activator; Pyrimidone; Type 2 diabetes mellitus