PDE-10A inhibitors as insulin secretagogues.
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.
Cantin
Louis-David
LD
Department of Chemistry Research, Bayer Pharmaceuticals Corporation, West Haven, CT 06516, USA. Louis-David.Cantin.Cantin@astrazeneca.com
Magnuson
Steven
S
Gunn
David
D
Barucci
Nicole
N
Breuhaus
Marina
M
Bullock
William H
WH
Burke
Jennifer
J
Claus
Thomas H
TH
Daly
Michelle
M
Decarr
Lynn
L
Gore-Willse
Ann
A
Hoover-Litty
Helana
H
Kumarasinghe
Ellalahewage S
ES
Li
Yaxin
Y
Liang
Sidney X
SX
Livingston
James N
JN
Lowinger
Timothy
T
Macdougall
Margit
M
Ogutu
Herbert O
HO
Olague
Alan
A
Ott-Morgan
Ronda
R
Schoenleber
Robert W
RW
Tersteegen
Adrian
A
Wickens
Philip
P
Zhang
Zhonghua
Z
Zhu
Jian
J
Zhu
Lei
L
Sweet
Laurel J
LJ
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
D007328:Insulin; D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; C037219:quinoline; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases