Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties

Abstract

A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.

Targeting the dopamine D1 receptor or its downstream signalling by inhibiting phosphodiesterase‐1 improves cognitive performance

“…One main finding of this study is the pro-cognitive effect of PDE1 inhibition, that is, that ITI-214 reverses MK-801-induced working memory impairments in the T-maze continuous alternation task, in line with a recent report demonstrating that ITI-214 enhances acquisition, consolidation and retrieval memory processes in the novel object recognition task (Snyder et al, 2016;Dyck et al, 2017). In the present study, the response to different doses of ITI-214 suggests an inverted U-shaped dose-response, an observation also made by Snyder et al (2016), consistent with the idea that optimal cognitive performance requires optimal engagement of prefrontal dopamine signal transduction (Goldman-Rakic et al, 2000).…”

An EPAC1/PDE1C-Signaling Axis Regulates Formation of Leading-Edge Protrusion in Polarized Human Arterial Vascular Smooth Muscle Cells

“…Interestingly, while selective inhibition of HASMC PDE3 activity with cilostamide (5 µM) [1,22] reduced LEP formation in HASMCs, PDE4 inhibition with Ro 20-1724 (10 µM) did not (Table 3). Unexpectedly, pharmacological inhibition of PDE1 activity (C33, 1 µM) [23,24] in these cells markedly promoted the formation of LEPs in our experiments (Table 3). Although HASMCs have been reported by us and others to express both PDE1A and PDE1C gene-encoded enzymes, since PDE1C preferentially hydrolyzes cAMP compared to PDE1A, we next investigated the possibility that PDE1 inhibitors acted by inhibiting cAMP hydrolysis by PDE1C.…”

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…ITI-214 demonstrates cognition-enhancing effects in rodent models of long-term memory and working memory deficits (95)(96)(97), mimicking effects of a dopamine receptor 1 (D1) agonist (97) and occurring at doses that leave efficacy of the antipsychotic risperidone intact (95). Although the target mediating the cognition-enhancing effects of ITI-214 remains undetermined, PDE1B may be the most likely candidate given its expression in D1-expressing neurons (97) along with the fact that the a PDE1B-selective inhibitor showed similar cognition-enhancing effects (98). ITI-214 was moved into the clinic, with potential applications for cognitive deficits associated with schizophrenia, AD, and Parkinson's Disease (96), with safety and tolerability established in healthy volunteers and patients with schizophrenia (Table 3).…”