title: Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis).
abstract: Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.
authors: Dept. of Neuroscience and CNS Safety Pharmacology, Maccine Pte Ltd, Singapore, Singapore.
authors: Jane S
authors: JS
authors: Sutcliffe
authors: CHDI Foundation/CHDI Management Inc., Los Angeles, California, United States of America.
authors: Vahri
authors: V
authors: Beaumont
authors: Dept. of Neuroscience and CNS Safety Pharmacology, Maccine Pte Ltd, Singapore, Singapore.
authors: James M
authors: JM
authors: Watson
authors: Dept. of Neuroscience and CNS Safety Pharmacology, Maccine Pte Ltd, Singapore, Singapore.
authors: Chang Sing
authors: CS
authors: Chew
authors: CHDI Foundation/CHDI Management Inc., Los Angeles, California, United States of America.
authors: Maria
authors: M
authors: Beconi
authors: Dept. of Neuroscience and CNS Safety Pharmacology, Maccine Pte Ltd, Singapore, Singapore.
authors: Daniel M
authors: DM
authors: Hutcheson
authors: CHDI Foundation/CHDI Management Inc., Los Angeles, California, United States of America.
authors: Celia
authors: C
authors: Dominguez
authors: CHDI Foundation/CHDI Management Inc., Los Angeles, California, United States of America.
authors: Ignacio
authors: I
authors: Munoz-Sanjuan
mesh_terms: D061605:Administration, Intravenous; D000494:Allosteric Regulation; D000818:Animals; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004353:Drug Evaluation, Preclinical; D005260:Female; D008252:Macaca fascicularis; D018697:Nootropic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020889:Rolipram / Q000494:pharmacology
chemical_list: D001559:Benzhydryl Compounds; C000596953:D159687; D018697:Nootropic Agents; D010671:Phenylurea Compounds; D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram