Pyrazoloquinolines as PDE10A inhibitors: discovery of a tool compound.
A series of pyrazoloquinolines, possessing (hetero)arylhydroxymethyl substituents at the quinoline C-4 position were evaluated as PDE10A inhibitors. Among these, methylpyrimidyl analogue 15 was identified as having good rodent and monkey exposure, and a MED of 10 mg/kg in an in vivo model.
Department of Chemical Research-CV & CNS, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. william.mcelroy@merck.com
William T
WT
McElroy
Zheng
Z
Tan
Kallol
K
Basu
Shu-Wei
SW
Yang
Jennifer
J
Smotryski
Ginny D
GD
Ho
Deen
D
Tulshian
William J
WJ
Greenlee
Deborra
D
Mullins
Mario
M
Guzzi
Xiaoping
X
Zhang
Carina
C
Bleickardt
Robert
R
Hodgson
D000818:Animals; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000882:Haplorhini; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D047069:Pyrazolones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
D004791:Enzyme Inhibitors; D047069:Pyrazolones; D011804:Quinolines; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases