title: Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.
abstract: The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States. Electronic address: douglas.burdi@sunovion.com.
authors: Douglas F
authors: DF
authors: Burdi
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: John E
authors: JE
authors: Campbell
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Jun
authors: J
authors: Wang
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Sufang
authors: S
authors: Zhao
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Hua
authors: H
authors: Zhong
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Jianfeng
authors: J
authors: Wei
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Una
authors: U
authors: Campbell
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Liming
authors: L
authors: Shao
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Lee
authors: L
authors: Herman
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Patrick
authors: P
authors: Koch
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Philip G
authors: PG
authors: Jones
authors: Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, United States.
authors: Michael C
authors: MC
authors: Hewitt
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010622:Phencyclidine; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D014230:Triazoles; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D010622:Phencyclidine
keywords: PCP-induced hyperlocomotion; PDE10A; PDE10A inhibitor; Phosphodiesterase inhibitor; Schizophrenia