Novel triazines as potent and selective phosphodiesterase 10A inhibitors.
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).
Pfizer Neuroscience Princeton, 865 Ridge Road, Monmouth Junction, NJ 08852, USA. malamas.michael@gmail.com
Michael S
MS
Malamas
Hans
H
Stange
Rudolf
R
Schindler
Hans-Joachim
HJ
Lankau
Christian
C
Grunwald
Barbara
B
Langen
Ute
U
Egerland
Thorsten
T
Hage
Yike
Y
Ni
James
J
Erdei
Kristi Yi
KY
Fan
Kevin
K
Parris
Karen L
KL
Marquis
Steve
S
Grauer
Julie
J
Brennan
Rachel
R
Navarra
Radka
R
Graf
Boyd L
BL
Harrison
Albert
A
Robichaud
Thomas
T
Kronbach
Menelas N
MN
Pangalos
Nicholas J
NJ
Brandon
Norbert
N
Hoefgen
D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D014227:Triazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D016291:Dizocilpine Maleate; C119843:PDE10A protein, human; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases