The discovery of potent, selective, and orally active pyrazoloquinolines as PDE10A inhibitors for the treatment of Schizophrenia.
High-throughput screening identified a series of pyrazoloquinolines as PDE10A inhibitors. The SAR development led to the discovery of compound 27 as a potent, selective, and orally active PDE10A inhibitor. Compound 27 inhibits MK-801 induced hyperactivity at 3mg/kg with an ED(50) of 4mg/kg and displays a ∼6-fold separation between the ED(50) for inhibition of MK-801 induced hyperactivity and hypolocomotion in rats.
Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA. ginny.ho@merck.com; ginny.ho@spcorp.com
Ginny D
GD
Ho
Shu-Wei
SW
Yang
Jennifer
J
Smotryski
Ana
A
Bercovici
Terry
T
Nechuta
Elizabeth M
EM
Smith
William
W
McElroy
Zheng
Z
Tan
Deen
D
Tulshian
Brian
B
McKittrick
William J
WJ
Greenlee
Alan
A
Hruza
Li
L
Xiao
Diane
D
Rindgen
Deborra
D
Mullins
Mario
M
Guzzi
Xiaoping
X
Zhang
Carina
C
Bleickardt
Robert
R
Hodgson
D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D047069:Pyrazolones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D047069:Pyrazolones; D011804:Quinolines; D016291:Dizocilpine Maleate; C119843:PDE10A protein, human; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases