Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Figures & data

Figure 1. Overview of the specificity of PDE1 to PDE11 for cAMP and/or cGMP. Reproduced with permission from [5].

Figure 2. Mechanism of action of PDE inhibitors. An extracellular signal (e.g. neurotransmitter or hormone) activates adenylate cyclase (AC) and guanylate cyclase (GC), which produce their corresponding cyclic nucleotides out of ATP and GTP, respectively. cAMP activates protein kinase A (PKA) and cGMP activates protein kinase G (PKG). Both PKA and PKG can phosphorylate other enzymes or transcription factors such as CREB in the nucleus. Besides gene expression, cAMP and cGMP also regulate cAMP- and cGMP-gated ion channels, respectively, which depolarize the synaptic terminals. Eventually, these processes will result in a cellular response, e.g. neurotransmitter release, receptor trafficking, synapse formation, dendritic formation or neurogenesis. Phosphodiesterases (PDEs) hydrolyze cAMP and/or cGMP leading to the formation of the inactive 5ʹ-cAMP and 5ʹ-cGMP, respectively. PDE inhibitors are selective for cAMP and/or cGMP degrading PDEs, and thus can specifically influence the cellular response of a biological system, in this case brain circuitry implicated in cognitive processes and neuroprotection.

Table 1. Overview of the changes in mRNA expression levels per subtype of PDE (gene product if known) in the hippocampus/temporal cortex of AD patients.

PDE subtype	Brain structure	Changes in expression	References
PDE1	–	–	–
PDE2	Hippocampus	No change	[21]
PDE3	–	–	–
PDE4A	–	–	–
PDE4B	–	–	–
PDE4C	–	–	–
PDE4D	Hippocampus	D1,2↑/D3,5,6,7,8,9↓	[22]
PDE5	Hippocampus	↓?	[21]
	Temporal cortex	↑	[23]
PDE7A	Hippocampus	↓	[24]
PDE7B	Hippocampus	No change	[24]
PDE8A	Hippocampus	↓?	[24]
PDE8B	Hippocampus	↑	[24]
PDE9	Hippocampus	No change	[21]
	Temporal cortex	No change	[23]
PDE10A	Temporal cortex	No change	[23]
PDE11	–	–	–

↑: increase reported; ↓: decrease reported; ↓?: questionable decrease reported (detection limit). – Not studied yet. Of note, PDE6 is not mentioned since it is only expressed in the retina and pineal gland.

Table 2. Overview of clinical studies on the effects of different PDE inhibitors on cognitive (memory) performance in adults, elderly, and patients with MCI or AD.

Agent (Sponsor)	Dosing, treatment (always oral)	Subjects	Status	Results	ClinicalTrials.gov identifier/reference
PDE1
Vinpocetine (University of Leeds, UK)	10, 20, 40 mg daily for 3 days	Healthy females	Completed (Phase II)	Sternberg Memory Scanning Test + (only the 40 mg dose)	[28]
Vinpocetine as ingredient in SPRINT (Nootrobox)	40 mg single administration	Healthy young adults	Not yet open for participant recruitment (Phase IV)	Not yet available	NCT02857829
Vinpocetine/Ginko biloba compound (The Scripps Research Institute, USA)	10 mg three times daily for 2 weeks	Healthy adults	Completed (Phase II)	Cognometer Test Battery +?	[29]
Vinpocetine as ingredient in Cognitex (Tel-Aviv Sourasky Medical Center/Enzymotec)	20 mg daily for 12 weeks	Elderly with memory complaints	Completed (Phase IV)	Cognition +?	NCT00719953, [30]
Vinpocetine (BAZ County Hospital and University Teaching Hospital, Miskolc, Hungary)	Undisclosed dosing for 18 months	MCI patients	Completed (Phase II)	MMSE, ADAS-Cog +	[31]
Vinpocetine (VA Medical Center San Diego, USA)	30, 45, 60 mg daily for 1 year	Alzheimer’s disease patients	Completed (Phase II)	Cognition =	[32,33]
PDE3
Cilostazol (Juntendo University School of Medicine, Tokyo, Japan)	100 mg daily for 1–13 months as add-on to 5 mg donepezil	Mild to moderate Alzheimer’s disease patients	Completed (Phase IV)	MMSE +	[34]
Cilostazol (Tokyo Medical University, Japan)	100 mg daily for 6 months	Patients with Alzheimer’s disease and cerebrovascular disease	Completed (Phase IV)	ADAS-cog, Revised Wechsler Memory Scale +	[35]
Cilostazol (Seoul National University Hospital/Korea OIAA)	200 mg daily for 24 weeks as add-on to 10 mg donepezil	Mild to moderate Alzheimer’s disease patients with subcortical white matter hyperintensities	Completed (Phase IV)	MMSE, ADAS-cog =	NCT01409564
Cilostazol (Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan)	50 mg twice daily for 12 months as add-on to AChEIs (types and doses undisclosed)	Patients with Alzheimer’s disease	Completed (Phase II)	MMSE, CDR-SB +	[36]
Cilostazol (Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan)	50–100 mg daily for at least 3 months (retrospectively)	Elderly	Completed (Phase II)	Reduced risk incidence of dementia including Alzheimer’s disease, mainly in cilostazol users with ischemic heart disease and cerebral vascular disease	[37]
Cilostazol (National Cerebral and Cardiovascular Center Hospital, Osaka, Japan)	Average 130 mg daily for at least 6 months (retrospectively)	Elderly, MCI patients and demented patients	Completed (Phase IV)	MMSE + (only in MCI patients)	[38]
Cilostazol (National Cerebral and Cardiovascular Center Hospital, Osaka, Japan)	Average 121 mg daily for at least 6 months with donepezil (dose undisclosed) (retrospectively)	Mild Alzheimer’s disease patients and moderate/severe Alzheimer’s patients on donepezil	Completed (Phase IV)	MMSE + (only in mild Alzheimer’s patients)	[39]
Cilostazol (National Cerebral and Cardiovascular Center Hospital, Osaka, Japan)	50 mg twice daily for 96 days	MCI patients	Currently recruiting participants (Phase II)	Not yet available	NCT02491268
PDE4
MEM 1414 (Memory Pharmaceuticals/Roche)	Undisclosed	Healthy adults and healthy elderly	Completed (Phase I)	Safety +	[40]
MK-0952 (Merck)	Undisclosed	Patients with mild to moderate Alzheimer’s disease	Terminated (Phase II)	Undisclosed	NCT00362024
HT-0712 (DART Neuroscience)	45 mg daily for 28 days	Elderly with age-associated memory impairment	Completed (Phase II)	Verbal learning (delayed recall) +	[41]
HT-0712 (DART Neuroscience)	50 mg daily for 6 weeks	Elderly with age-associated memory impairment	Completed (Phase II)	Undisclosed	NCT02013310
Roflumilast (Takeda)	Undisclosed doses, single administration with or without donepezil (10 mg)	Healthy adults with scopolamine-Induced cognitive deficits	Completed (Phase I)	Verbal learning (immediate recall) + (only the combination treatment)	NCT02051335
Roflumilast (Maastricht University, The Netherlands)	0.1, 0.3, 1 mg single administration	Healthy young adults	Completed (Phase II)	Verbal learning (immediate recall) + (only the 0.1 mg dose) Sensory gating + (only the 0.1 mg dose)	NCT01433666, [42]
Roflumilast (Maastricht University, The Netherlands /Takeda)	0.1, 0.25, 1 mg single administration	Healthy elderly and elderly with age-associated memory impairment	Completed (Phase II)	Undisclosed	ISRCTN registry ID ISRCTN96013814; EudraCT Number 2013–001223-39
BPN14770 (Tetra Discovery Partners)	10, 20 mg and one undisclosed high dose twice daily for 2 weeks	Healthy adults and Healthy elderly	Completed (Phase I)	Safety +	NCT02648672, NCT02840279, [43]
BPN14770 (Tetra Discovery Partners)	10, 20 mg and one undisclosed high dose twice daily for 2 weeks	Healthy elderly	Complete (Phase I)	Working memory + (10 and 20 mg dose)	NCT02840279, [43]
Denbufylline (Tel Aviv University, Israel)	25, 50, 100 mg twice daily for 16 weeks	Patients with vascular, mixed or Alzheimer’s disease	Completed (Phase II)	MMSE + (only when combining all dosages and treatment groups)	[44]
Denbufylline (University of Vienna, Austria)	100 mg twice daily for 12 weeks	Patients with multi-infarct dementia and Alzheimer’s disease	Completed (Phase II)	CGI +	[45]
PDE5
Sildenafil (University of Cologne, Germany)	100 mg single administration	Healthy males	Completed (Phase IV)	Cognition =	[46]
Sildenafil (Hannover Medical School, Germany)	100 mg single administration	Healthy males	Completed (Phase IV)	Cognition =	[47]
Vardenafil (Maastricht University, The Netherlands)	10, 20 mg single administration	Healthy young adults	Completed (Phase II)	Sensory gating =	[48]
Vardenafil (Maastricht University, The Netherlands)	10, 20 mg single administration	Healthy young adults	Completed (Phase II)	Cognition =	[49]
Tadalafil (St George’s, University of London, UK)	20 mg single administration	Elderly with small vessel disease not diagnosed with dementia	Recruiting participants (Phase II)	Not yet available	NCT02450253
PDE9
PF-04447943 (Pfizer)	25 mg daily for 12 weeks	Patients with mild to moderate Alzheimer’s disease	Completed (Phase II)	Cognition =	[50]
BI 409,306 (Boehringer Ingelheim)	Undisclosed doses for 12 weeks	Alzheimer’s disease patients	Completed (Phase II)	Not yet available	NCT02337907

In case of data reported: +: positive effects; =: no effect reported; +?: questionable positive effect due to drug constraints (PDE1); MMSE: mini-mental state examination; ADAS-cog: Alzheimer’s disease assessment scale (cognitive part); CGI: Clinical Global Impression; CDR-SB: clinical dementia rating sum of boxes; AChEIs: Acetylcholinesterase inhibitors.

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