title: Use of structure-based design to discover a potent, selective, in vivo active phosphodiesterase 10A inhibitor lead series for the treatment of schizophrenia.
abstract: Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States. chris.j.helal@pfizer.com
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Helal
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Kang
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Chappie
authors.forename: John M
authors.initials: JM
authors.lastname: Humphrey
authors.forename: Eric S
authors.initials: ES
authors.lastname: Marr
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Fennell
authors.forename: Lois K
authors.initials: LK
authors.lastname: Chenard
authors.forename: Carol
authors.initials: C
authors.lastname: Fox
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.forename: Robert D
authors.initials: RD
authors.lastname: Williams
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Chapin
authors.forename: Judith
authors.initials: J
authors.lastname: Siuciak
authors.forename: Lorraine
authors.initials: L
authors.lastname: Lebel
authors.forename: Frank
authors.initials: F
authors.lastname: Menniti
authors.forename: Julia
authors.initials: J
authors.lastname: Cianfrogna
authors.forename: Kari R
authors.initials: KR
authors.lastname: Fonseca
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Nelson
authors.forename: Rebecca
authors.initials: R
authors.lastname: O'Connor
authors.forename: Mary
authors.initials: M
authors.lastname: MacDougall
authors.forename: Laura
authors.initials: L
authors.lastname: McDowell
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000378:metabolism; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010539:Permeability; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D010726:Phosphodiesterase Inhibitors; C119843:PDE10A protein, human; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP