title: Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia.
abstract: We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.
authors.affiliation: Neuroscience, Pfizer Global Research and Development, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA. Christopher.j.schmidt@pfizer.com
authors.forename: C J
authors.initials: CJ
authors.lastname: Schmidt
authors.forename: D S
authors.initials: DS
authors.lastname: Chapin
authors.forename: J
authors.initials: J
authors.lastname: Cianfrogna
authors.forename: M L
authors.initials: ML
authors.lastname: Corman
authors.forename: M
authors.initials: M
authors.lastname: Hajos
authors.forename: J F
authors.initials: JF
authors.lastname: Harms
authors.forename: W E
authors.initials: WE
authors.lastname: Hoffman
authors.forename: L A
authors.initials: LA
authors.lastname: Lebel
authors.forename: S A
authors.initials: SA
authors.lastname: McCarthy
authors.forename: F R
authors.initials: FR
authors.lastname: Nelson
authors.forename: C
authors.initials: C
authors.lastname: Proulx-LaFrance
authors.forename: M J
authors.initials: MJ
authors.lastname: Majchrzak
authors.forename: A D
authors.initials: AD
authors.lastname: Ramirez
authors.forename: K
authors.initials: K
authors.lastname: Schmidt
authors.forename: P A
authors.initials: PA
authors.lastname: Seymour
authors.forename: J A
authors.initials: JA
authors.lastname: Siuciak
authors.forename: F D
authors.initials: FD
authors.lastname: Tingley
authors.forename: R D
authors.initials: RD
authors.lastname: Williams
authors.forename: P R
authors.initials: PR
authors.lastname: Verhoest
authors.forename: F S
authors.initials: FS
authors.lastname: Menniti
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C528913:2-(4-(pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)phenoxymethyl)quinoline succinic acid; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D011994:Recombinant Proteins; D000242:Cyclic AMP; C512064:PDE10A protein, rat; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D004298:Dopamine