title: Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition.
abstract: In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7mg/kg (p.o.), corresponding to plasma and brain exposures of 28ng/mL and 43ng/g, respectively. Using microdialysis, we show that 3mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3mg/kg (p.o.) corresponding to 59-86% occupancy. At similar doses in a catalepsy study, the time on the bar was increased but the maximal effect was less than that seen with haloperidol. In an EEG study, 3 and 10mg/kg (p.o.) SEP-39 suppressed REM intensity and increased the latency to REM sleep. We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications.
authors.affiliation: Discovery and Preclinical Research, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA. Electronic address: philip.jones@sunovion.com.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Jones
authors.affiliation: Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hewitt
authors.affiliation: Epizyme Inc., 400 Technology Square 4th Floor, Cambridge, MA 02139, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Retrophin Inc., 301 Binney St. 3rd floor, Cambridge, MA 02142, USA.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Quinton
authors.affiliation: Discovery and Preclinical Research, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Engel
authors.affiliation: Translational Medicine and Early Development, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lew
authors.affiliation: Translational Medicine and Early Development, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA.
authors.forename: Una
authors.initials: U
authors.lastname: Campbell
authors.affiliation: Discovery and Preclinical Research, Sunovion Pharmaceuticals, 84 Waterford Drive, Marlborough, MA 01752, USA.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Burdi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D003071:Cognition / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects; D012895:Sleep, REM / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D001562:Benzimidazoles; D010726:Phosphodiesterase Inhibitors; C000606478:SEP-39 compound; D014230:Triazoles; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D006220:Haloperidol
keywords: EEG; Microdialysis; Phosphodiesterase 10A; Striatum