title: PDE-10A inhibitors as insulin secretagogues.
abstract: Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
authors.affiliation: Department of Chemistry Research, Bayer Pharmaceuticals Corporation, West Haven, CT 06516, USA. Louis-David.Cantin.Cantin@astrazeneca.com
authors.forename: Louis-David
authors.initials: LD
authors.lastname: Cantin
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
authors.forename: David
authors.initials: D
authors.lastname: Gunn
authors.forename: Nicole
authors.initials: N
authors.lastname: Barucci
authors.forename: Marina
authors.initials: M
authors.lastname: Breuhaus
authors.forename: William H
authors.initials: WH
authors.lastname: Bullock
authors.forename: Jennifer
authors.initials: J
authors.lastname: Burke
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Claus
authors.forename: Michelle
authors.initials: M
authors.lastname: Daly
authors.forename: Lynn
authors.initials: L
authors.lastname: Decarr
authors.forename: Ann
authors.initials: A
authors.lastname: Gore-Willse
authors.forename: Helana
authors.initials: H
authors.lastname: Hoover-Litty
authors.forename: Ellalahewage S
authors.initials: ES
authors.lastname: Kumarasinghe
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Li
authors.forename: Sidney X
authors.initials: SX
authors.lastname: Liang
authors.forename: James N
authors.initials: JN
authors.lastname: Livingston
authors.forename: Timothy
authors.initials: T
authors.lastname: Lowinger
authors.forename: Margit
authors.initials: M
authors.lastname: Macdougall
authors.forename: Herbert O
authors.initials: HO
authors.lastname: Ogutu
authors.forename: Alan
authors.initials: A
authors.lastname: Olague
authors.forename: Ronda
authors.initials: R
authors.lastname: Ott-Morgan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schoenleber
authors.forename: Adrian
authors.initials: A
authors.lastname: Tersteegen
authors.forename: Philip
authors.initials: P
authors.lastname: Wickens
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Laurel J
authors.initials: LJ
authors.lastname: Sweet
mesh_terms: D015195:Drug Design; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007328:Insulin; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; C037219:quinoline; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases