title: Highly potent, selective, and orally active phosphodiesterase 10A inhibitors.
abstract: The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
authors: Pfizer Neuroscience Princeton, NJ 08852, USA. malamas.michael@gmail.com
authors: Michael S
authors: MS
authors: Malamas
authors: Yike
authors: Y
authors: Ni
authors: James
authors: J
authors: Erdei
authors: Hans
authors: H
authors: Stange
authors: Rudolf
authors: R
authors: Schindler
authors: Hans-Joachim
authors: HJ
authors: Lankau
authors: Christian
authors: C
authors: Grunwald
authors: Kristi Yi
authors: KY
authors: Fan
authors: Kevin
authors: K
authors: Parris
authors: Barbara
authors: B
authors: Langen
authors: Ute
authors: U
authors: Egerland
authors: Thorsten
authors: T
authors: Hage
authors: Karen L
authors: KL
authors: Marquis
authors: Steve
authors: S
authors: Grauer
authors: Julie
authors: J
authors: Brennan
authors: Rachel
authors: R
authors: Navarra
authors: Radka
authors: R
authors: Graf
authors: Boyd L
authors: BL
authors: Harrison
authors: Albert
authors: A
authors: Robichaud
authors: Thomas
authors: T
authors: Kronbach
authors: Menelas N
authors: MN
authors: Pangalos
authors: Norbert
authors: N
authors: Hoefgen
authors: Nicholas J
authors: NJ
authors: Brandon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D006868:Hydrolysis; D006948:Hyperkinesis / Q000188:drug therapy; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D007527:Isoenzymes; D008024:Ligands; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011994:Recombinant Proteins; D000242:Cyclic AMP; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP