TY - JOUR
T1 - Novel triazines as potent and selective phosphodiesterase 10A inhibitors
AU - Malamas, Michael S.
AU - Stange, Hans
AU - Schindler, Rudolf
AU - Lankau, Hans Joachim
AU - Grunwald, Christian
AU - Langen, Barbara
AU - Egerland, Ute
AU - Hage, Thorsten
AU - Ni, Yike
AU - Erdei, James
AU - Fan, Kristi Yi
AU - Parris, Kevin
AU - Marquis, Karen L.
AU - Grauer, Steve
AU - Brennan, Julie
AU - Navarra, Rachel
AU - Graf, Radka
AU - Harrison, Boyd L.
AU - Robichaud, Albert
AU - Kronbach, Thomas
AU - Pangalos, Menelas N.
AU - Brandon, Nicholas J.
AU - Hoefgen, Norbert
PY - 2012/9/15
Y1 - 2012/9/15
N2 - 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 (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 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 = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg).
AB - 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 (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 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 = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg).
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U2 - 10.1016/j.bmcl.2012.07.076
DO - 10.1016/j.bmcl.2012.07.076
M3 - Article
C2 - 22902656
AN - SCOPUS:84865487391
SN - 0960-894X
VL - 22
SP - 5876
EP - 5884
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 18
ER -