Novel Phosphodiesterase Inhibitors for Cognitive Improvement in

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Novel Phosphodiesterase Inhibitors for Cognitive Improvement in Alzheimer’s Disease Yinuo Wu, Zhe Li, Yiyou Huang, Deyan Wu, and Hai-Bin Luo J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.7b01370 • Publication Date (Web): 24 Jan 2018 Downloaded from http://pubs.acs.org on January 24, 2018

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Journal of Medicinal Chemistry

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Novel Phosphodiesterase Inhibitors for Cognitive Improvement in

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Alzheimer’s Disease

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Yinuo Wu, Zhe Li, Yiyou Huang, Deyan Wu, and Hai-Bin Luo*

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School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China

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Abstract：：

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Alzheimer’s disease (AD) is one of the greatest public health challenges. Phosphodiesterases (PDEs)

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are a super enzyme family responsible for the hydrolysis of two second messengers cyclic adenosine

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monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Since several PDE

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subfamilies are highly expressed in the human brain, the inhibition of PDEs is involved in

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neurodegenerative processes by regulating the concentration of cAMP and/or cGMP. Currently,

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PDEs are considered as promising targets for the treatment of AD since many PDE inhibitors have

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exhibited remarkable cognitive improvement effects in preclinical studies and over fifteen of them

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have been subjected to clinical trials. The aim of this review is to summarize the outstanding

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progress that has been made by PDE inhibitors as anti-AD agents with encouraging results in

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preclinical studies and clinical trials. The binding affinity, pharmacokinetics, underlying mechanisms,

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and limitations of these PDE inhibitors in the treatment of AD are also reviewed and discussed.

17 18

1. Introduction

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Alzheimer's disease (AD) is the most common type of dementia, which is characterized by

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progressive memory loss, a decline in language skills, and some other neurodegenerative disorders.1

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According to the data provided by the Alzheimer's Association (USA), approximately 46.8 million

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people worldwide are suffering from AD. The morbidity and mortality rates of patients with AD are ACS Paragon Plus Environment 1

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high, especially for elderly individuals over the age of 60. The global societal economic cost for AD

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patients was estimated at $818 billion in 2015 and is expected to rise to $1 trillion in 2018 and $2

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trillion in 2030.2 Thus, AD has become one of the greatest public health challenges across the world

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and severely impacts individuals and their families.

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Currently, the clinically available anti-AD drugs are three acetylcholine inhibitors (donepezil,

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rivastigmine, and galantamine) and one N-methyl-D-aspartate receptor (NMDA) antagonist

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(memantine),3 and these drugs improve only cognition and the degree of dementia in AD patients but

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do not reverse the progression of AD. Thus, the need to develop novel anti-AD drugs is extremely

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compelling. While the pathogenic mechanism of AD is highly complicated and still not fully

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understood, several hypotheses about the pathophysiology of AD, including low levels of

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acetylcholine, deposition of β-amyloid (Aβ) plaques, aggregation of Tau-protein, oxidative stress,

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and the accumulation of biometals, have been proposed to facilitate drug development.4 Recently, the

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Aβ pathological hypothesis has attracted great interest from many studies, as Aβ-plaques and

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neurofibrillary tangles are two major hallmarks in the brains of AD patients. However, several

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promising candidates targeting Aβ, such as bapineuzumab and solanuzumab, have failed in Phase III

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clinical trials.5 Although limited information was obtained for the failure, one important possible

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reason is that treatment of symptomatic dementia such as β-amyloid (Aβ) plaques was too late to

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delay the progression of the AD.6 Furthermore, approximately 20-25% of patients have been

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observed with the assistance of positron emission tomography imaging to be without Aβ burden.7

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Thus, the discovery of anti-AD agents, including non-Aβ-directed therapies, still has a long way to

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go.

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Phosphodiesterases (PDEs) are a super enzyme family that are responsible for the hydrolysis of

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two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine ACS Paragon Plus Environment 2

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monophosphate (cGMP).8 The PDE superfamily is coded by 21 identified genes and can be divided

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into 11 subtypes (PDE1-11). Among these subtypes, PDEs 4, 7, and 8 specifically hydrolyze cAMP,

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whereas PDEs 5, 6, and 9 specifically hydrolyze cGMP. The remaining PDE families are capable of

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degrading both cGMP and cAMP.9 As cAMP and cGMP are essential in cellular signaling and

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function, PDE inhibitors are used to regulate many biological processes by increasing the cellular

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levels of cAMP and cGMP. Thus far, several PDE inhibitors have been approved as therapeutics for

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the treatment of erectile dysfunction, pulmonary hypertension, chronic obstructive pulmonary

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disease, and heart failure (Table 1).10 The most successful example of this drug class is sildenafil, a

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PDE5 inhibitor that is used for the treatment of male erectile dysfunction (Viagra) and pulmonary

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hypertension (Revatio).

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PDEs are highly expressed in the human brain, and their inhibitors regulate neurodegenerative

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processes by increasing the concentrations of cAMP and cGMP in brain tissue (Figure 1).11 In

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general, cAMP is synthesized from ATP by adenylate cyclase (AC), activates protein kinase A (PKA)

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and phosphorylates cAMP-responsive element binding protein (CREB), which has been considered a

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molecular switch required for learning and memory. Several preclinical and clinical studies have

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demonstrated that impaired CREB phosphorylation plays an important role in neurodegenerative

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disorders, especially AD.12 Decreasing the level of cAMP may cause a decreased concentration of

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CREB, which affects the transcription of genes related to synaptic plasticity and survival, such as

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brain-derived neurotrophic factor (BDNF), and resulting in the loss of synaptic plasticity and in

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memory decline in AD.13 Similarly, cGMP, which is derived from GTP by guanylyl cyclase (GC),

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could be activated by nitric oxide (NO) via the NO/cGMP pathway, which activates protein kinase G

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(PKG) and subsequent CREB phosphorylation, thus increasing the level of the antiapoptotic protein

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Bcl-2.14,15 ACS Paragon Plus Environment 3


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Since the first preclinical AD study on the PDE4 inhibitor, rolipram, which indicated that the

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inhibition of PDEs might have promising effects on the improvement of the memory deficits in

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AD,15 several PDE inhibitors have exhibited remarkable effects in animal models related to AD,

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including the Morris water maze, passive avoidance, and object recognition tasks (Table 2). In view

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of the encouraging results obtained in preclinical studies, several PDE inhibitors have been subjected

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to clinical trials for the treatment of cognitive disorders in AD patients (Table 3). Most of these

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inhibitors exhibited outstanding safety and tolerability profiles in Phase I studies. Furthermore, over

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ten PDE inhibitors have been subjected to Phase II/III/IV clinical trials. Thus, this review mainly

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focuses on the outstanding progress that has been made in the application of PDE inhibitors for

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memory enhancement effects for anti-AD purposes in preclinical or clinical trials.

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Table 1. PDEs inhibitors approved on the market. Compound Vinpocetine

Drug name Calan®, Cavinton®

Target PDE1

Clinical use Parkinson' s disease Alzheimer disease

Cilostazol

Amrinone Lactate

Pletal®, Pletaal® Inocor®

PDE3 PDE3

Anti-platelet, intermittent claudication Heart failure

ilrinone Lactate

Primacor®

PDE3

Congestive heart failure

Roflumilast Apremilast Crisaborole Sildenafil Citrate

Daxas® Daliresp® Otezla® Eucrisa® Viagra®

PDE4 PDE4 PDE4 PDE5

Tadalafil

Cialis®

PDE5

Vardenafil Hydrochloride Avanafil

Vivanza®

PDE5

Chronic obstructive pulmonary disease Psoriasis and psoriatic arthritis Allergic dermatitis Erectile dysfunction, Pulmonary Arterial Hypertension Erectile dysfunction, Pulmonary Arterial Hypertension Erectile Dysfunction

Zepeed®, Stendra®

PDE5

Erectile Dysfunction

，

12 13 14

2. PDE inhibitors studied for the treatment of AD 2.1 . PDE1 inhibitors ACS Paragon Plus Environment 4

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PDE1 is a Ca2+/calmodulin-dependent PDE family with three isoforms (PDE1A, 1B, and 1C)

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that hydrolyzes both cGMP and cAMP.17 PDE1B and PDE1C are the two major isoforms existing in

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humans, while PDE1A has relatively low expression. Each isoform is also expressed in a

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tissue-specific manner. In the caudate nucleus and the nucleus accumbens, for example, PDE1B is

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the most abundant isoform among all PDE species, and the level of PDE1B is 10- and 100-fold

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higher than that of PDE1C and PDE1A, respectively. In the cortex and hippocampus, the levels of

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PDE1B and PDE1C are almost the same. In the periphery, PDE1C is the major isoform of PDE1 and

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mainly exists in the heart, bladder, and lungs (Figure S1).18 Its specific distribution in the brain and

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its distinctive regulation by intracellular calcium and calmodulin make PDE1 an attractive target to

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improve cognitive impairments in neurodegenerative diseases, such as AD, schizophrenia, and

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Parkinson’s disease.19

，

ACS Paragon Plus Environment 5


1 2

Figure 1: The relation of PDE inhibition and the cAMP or cGMP signaling pathway in the brain.

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PDE: phosphodiesterase; AC: adenyl cyclase; GC: guanylyl cyclase; ATP: adenosine triphosphate;

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GTP: guanosine triphosphate; PKA: protein kinase A; PKG: protein kinase G; P: phosphorylated;

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CREB: cAMP response element binding protein.

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1 2

Figure 2. Current PDE1 inhibitors for the treatment of AD.

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Vinpocetine (1), a derivative of the alkaloid vincamine, shows weak inhibition against PDE1

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(IC50: 30 µM) and has been widely used for the treatment of cognitive dysfunction (Figure 2).20, 21 In

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streptozotocin (STZ)-induced rat models, which closely simulate the clinical and pathologic features

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of sporadic AD22 (Table 2), chronic treatment with 1 significantly improved learning and memory

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abilities in the Morris water maze and passive avoidance tests. Furthermore, the levels of

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malondialdehyde (MDA) and nitrite decreased, whereas that of glutathione (GSH) increased. The

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concentrations of acetylcholinesterase and lactate dehydrogenase were also regulated by 1. These

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results suggested that its effect on memory impairment might be related to oxidative stress and

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cholinergic function mechanisms. Pharmacokinetics studies of patients with cerebrovascular

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disorders demonstrated that 1 is able to pass through the blood-brain barrier and reach the central

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nervous system.23 A clinical study of patients with mild to moderate organic psychosyndromes,

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including primary dementia, was carried out in 1991 to evaluate the efficacy and tolerance of orally

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administering 1. The result showed that 1 could efficiently enhance the cognitive performance of

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these patients.24

18 19

Table 2. PDEs inhibitors studied in the animal models of Alzheimer's disease. ACS Paragon Plus Environment 7


Compounds

Subject

Model

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Results

(No, its target)

Vinpocetine

Streptozotocin injected rats 22

(1, PDE1)

Morris water maze, 10 mg/kg,

Improve memory,

i.c.v.;

Reduce oxidative–nitritive stress,

Passive avoidance, 10 mg/kg, i.c.v. Modulate cholinergic functions,

Prevent Neuronal damage.

ITI-214

Rats 26

(2, PDE1)

BAY-60-7550

Chronic stress-induced mice 36

(4, PDE2)

Rats and C57BL/6J mice 31

Object recognition, 0.3-3.0 mg/kg,

Improve acquisition, consolidation, and

i.e.

retrieval memory.

Morris water maze, 3.0 mg/kg, i.p.; Reverse cognitive impairment via

Novel object recognition and

neuroplasticity-related

location task, 3.0 mg/kg, i.p.

NMDAR-CaMKII-cGMP/cAMP signaling.

Object recognition and social

Improve memory,

memory task, 1.0 mg/kg, p.o.

Enhance LTP,

Reversed MK801-induced deficits. Aged rats 33

APP/PS1 mice 35

Cilostazol

Aβ25–35-injected mice

Object recognition task, 0.3 mg/kg, Improve cognition and memory through

i.p.

enhancing the nNOS activity.

Object location test, 0.3 mg/kg,

Improve memory without anxiety,

p.o.;

depressive-like behavior or

Y- maze, 0.3 mg/kg, p.o.;

hypothalamusepituitaryeadrenal axis

Forced swim test, 0.3 mg/kg, p.o.;

regulation;

Elevated zero maze, 0.3 mg/kg,

No changes on the level of Aβ, pCREB ,

p.o.

BDNF or presynaptic density.

Y-maze, 30 mg/kg, p.o. 54;

Improve memory possibly due to the


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(8, PDE3)

Passive avoidance, 30 mg/kg, p.o.

prevention of oxidative damage51 or by

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decreasing Aβ accumulation by the reduction

;

Morris water maze, 10 mg/kg, i.p.55 of Aβ accumulation and tau phosphorylation.52

Rolipram

APP/PS1 mice 66

Morris water maze, 0.03 mg/kg,

Improve memory.

s.c.

(9, PDE4)

Radial-arm water maze, 0.03

mg/kg, s.c. Aβ25–35 or Aβ40 infused rats68, 71 Morris water maze, 0.5 mg/kg, i.p.; Improve memory; Passive avoidance, 0.5 and 1.25

Reduce oxidative–nitritive stress; Upregulate

mg/kg, i.p.

thioredoxin;

Inhibit iNOS/NO pathway.

Streptozotocin injected and

Morris water maze, 0.05 mg/kg and Improve memory probably due to its

aged mice72

0.1 mg/kg, i.p.

anti-cholinesterase, anti-amyloid,

anti-oxidative and anti-inflammatory effects Iron-impaired aged rat73

Object recognition, 0.01-0.1

Improve memory.

mg/kg, i.p.

Roflumilast

Mice 75

(10, PDE4)

Object location, 0.03 mg/kg, s.c.;

Improve memory,

Y-maze, 0.1 mg/kg, s.c.

Increased emetic-like properties at a dose

Xylazine/ketamine induced

100 times the memory-enhancing dose.

anaesthesia. Scopolamine-impaired rats 75

Object recognition, 0.1 mg/kg, i.p.

No improvement on memory when given

alone;



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Fully restored memory deficit when given in

combination with donepezil (0.1 mg/kg,

p.o.).

HT-0712

Aged mice 82

(11, PDE4)

MK-0952

Rats 84

(12, PDE4)

Fear conditioning, 0.1 mg/kg, i.p.;

Enhance long-term memory;

Morris water maze, 0.15 mg/kg,

Facilitate expression of CREB-regulated

i.p.

genes in aged hippocampus.

Object recognition, 0.01mg/kg,

Improve long-term recognition, memory and

i.p.;

cognition

Water maze delayed matching to

position test, 0.3mg/kg, i.p.

FFPM

APP/PS1 mice91

(14, PDE4)

GEBR-7b

Mice96

(15, PDE4)

Morris water maze, 0.5mg/kg, p.o.

Improve memory probably due to stimulation

Passive avoidance, 0.5mg/kg, p.o.

of the cAMP/PKA/CREB/BDNF pathway


and anti-inflammatory effects;

anaesthesia.

Little emetic potential.

Object location and recognition,

Improve memory at doses without

0.003 mg/kg, s.c.

emesis-like behavior.


anaesthesia.

D159687

Scopolamine-injected mice 98

Y-maze, 0.001mg/kg, i.v.

Improve memory at doses without

emesis-like behavior.

(17, PDE4) Mice 98

Object recognition , 0.01mg/kg, i.v.


anaesthesia.


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Sildenafil

Tg2576 mice107

(19, PDE5)

SAMP8 mice108

Morris water maze, 15 mg/kg, i.p.;

Reverse memory deficits by regulating the

Fear conditioning, 15 mg/kg, i.p.

Akt/GSK3b and p25/CDK5 pathways.

Morris water maze, 7.5 mg/kg, i.p.

Ameliorate age-dependent cognitive

impairments,

Reduce the Tau phosphorylation. APP/PS1 mice103,104

Fear conditioning, 3 mg/kg, i.p.

Improve memory by a long-lasting reduction

Reversal Morris water maze, 3

of Aβ levels.

mg/kg, i.p.

Object recognition, 10 mg/kg, i.p.

Restore cognitive deficits by the regulation

of PKG/pCREB signaling, anti-inflammatory

response and reduction of Aβ levels. SAMP8 and SAMR1 mice 109

Passive avoidance, 7.5 mg/kg, i.p.

Improve memory by reducing APP

processing, Aβ levels and tau

hyperphosphorylation.

Tadalafil

Aged J20-mice114

Morris water maze, 15 mg/kg, v.o.

(20, PDE5)

S14

Reduce Tau phosphorylation but not Aβ. APP/PS1 mice 116

Radial arm water maze, 3 mg/kg,

Improve memory.

i.p.

(23, PDE7)

BAY 73-6691

Improve memory;

Scopolamine-injected rats127

T-maze, 10 mg/kg, p.o.

(24, PDE9)

Passive avoidance, 10 mg/kg, p.o.


Improve long-term and short-term memory.


Rats128

Social recognition, 0.3 mg/kg, p.o.

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Improve both early and late LTP.

Object recognition, 0.1 mg/kg, p.o. Transform early into late LTP. Tg2576 mice129

Object location, 5 mg/kg, p.o.

Improve memory;

Restore Aβ induced impairment of long-term

potentiation.

PF-04447943

Aβ25–35-injected mice130

Morris water maze, 1 mg/kg, i.p.

Scopolamine-injected rats131

Conditioned avoidance attention, 3 Improve learning and memory.

Improve memory.

mg/kg, i.p.

(25, PDE9)

Object recognition,1 mg/kg, p.o. Mice131

Social recognition, 1 mg/kg, p.o.

Y-maze, 1 mg/kg, p.o.

1 2 3


Improve cognitive performance.

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1


Table 3. PDEs inhibitors in clinical trials for the treatment of Alzheimer's disease or related diseases. Compound

Target Condition

ITI-214 (2)

PDE1 Schizophrenia

Phase I, 2013, Terminated

NCT01900522

PF-0999

PDE2 Schizophrenia

Phase I, 2011, completed

NCT01429740

Healthy Volunteers


NCT01530529

PDE2 Healthy Volunteers


NCT02584569

Healthy Volunteers


NCT02461160

Phase IV, 2011, completed

NCT01409564

(PF-05180999, 6) TAK-915

Cilostazol (8)

Current status

PDE3 Alzheimer's Disease

Mild Cognitive Impairment Phase II, 2015, recruiting

Roflumilast (10)

PDE4 Dementia

Clinical trial registry no.

NCT02491268

Phase II, 2011, completed

NCT01433666

Phase I,2014, completed

NCT02051335

Preclinical, 2016, recruiting

NCT02835716


NCT02013310

Healthy Elderly Volunteers Phase I, 2010, terminated

NCT01215552

Memory Impairment, Alzheimer's Disease Alzheimer Disease HT-0712 (11)

PDE4 Age-Associated Memory Impairment

MK-0952 (12)


Phase II, 2006, terminated

NCT00362024

Etazolate (13)



NCT00880412

PDE4 Alzheimer Disease

Phase I, 2017, ongoing, but

NCT03030105

(EHT0202)

BPN14770 (18)

not recruiting participants.

Sildenafil (19)

Alzheimer's Disease


NCT02840279

Alzheimer's Disease


NCT02648672

Phase IV, 2007, completed

NCT00455715

Phase IV, 2013

NCT01941732


NCT02162979

PDE5 Schizophrenia Parkinson's Disease Parkinson's Disease

due to not enough subjects. PDE5 Dementia, Vascular

Phase II, 2017, recruting.

NCT02450253

PF-04447943 (25) PDE9 Alzheimer's Disease


NCT00930059

Tadalafil



Alzheimer's Disease


NCT00988598

Healthy


NCT01097876


Phase II, 2014, recruiting

NCT02240693

Alzheimer's Disease

Phase II, 2014, recruiting

NCT02337907

PF-02545920 (31) PDE10 Huntington's Disease


NCT02342548

Huntington's Disease


NCT02197130

BI-409306

1

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TAK-063 (32)

PDE10 Schizophrenia


NCT02477020

OMS643762

PDE10 Schizophrenia


NCT01952132

EVP-6308

PDE10 Schizophrenia


NCT02037074

a

Information from www.clinicaltrials.gov.

2 3

ITI-214 (2), a PDE1 inhibitor reported by Intra-Cellular Therapies in 2012, had an IC50 value of

4

0.058 nM against PDE1 and an excellent selectivity (>1000-fold) across other PDEs (Figure

5

2).25 The good pharmacokinetic properties of 2 made it suitable as a CNS drug candidate. In a novel

6

object recognition test in rats, with a single oral dose of 0.1-10 mg/kg, 2 could significantly enhance

7

memory performance during acquisition and consolidation without changing exploratory behavior or

8

basal locomotor activity. Furthermore, its administration did not change or have an effect on the

9

antipsychotic activity or pharmacokinetic profile of risperidone in the conditioned avoidance

10

response test.26 Currently, 2 has already completed four Phase I studies (Table 3), including a single

11

rising dose study in normal healthy volunteers and a multiple rising dose study once daily.27 Its

12

safety and tolerability in healthy volunteers and patients with schizophrenia have also been evaluated.

13

Although this trial has been terminated due to a business decision, the obtained results proved that 2

14

might work as an efficient candidate for the treatment of cognitive dysfunction as seen in AD,

15

schizophrenia, and Parkinson’s disease.

16

Most recently, a thienotriazolopyrimidinone PDE1 inhibitor, DNS-0056 (3), with good ACS Paragon Plus Environment 14

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1

pharmacokinetic properties and brain penetration has been developed (Figure 2).28 In a rat model of

2

recognition memory, 3 significantly increases long-term memory without altering exploratory

3

behavior in rats.

4 5

2.2 PDE2 inhibitors

6

Similar to PDE1, PDE2 is another subfamily that hydrolyzes both cAMP and cGMP. Unlike

7

other PDE families, in which activating cGMP signals could decrease the level of local cAMP, the

8

inhibition of PDE2 selectively abolishes the negative effects of cGMP on cAMP.29 PDE2A is the

9

only isoform of PDE2 that is highly expressed in most brain regions, including the caudate, nucleus

10

accumbens, cortex, and hippocampus (Figure S2).18 In most peripheral tissues, except the spleen, the

11

level of PDE2 is relatively low. This spatial distribution makes PDE2 inhibitors ideal as therapeutic

12

agents against cognitive disorder diseases but with less cardiovascular and other side effects that

13

commonly exist in other PDE inhibitors.30

14

15 16 17


18 19

BAY-60-7550 (4) is a highly selective PDE2 inhibitor developed by Bayer with an IC50 of 4.7

20

nM and up to 100-fold selectivity across other PDEs (Figure 3).30 Its poor pharmacokinetic ACS Paragon Plus Environment 15


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1

properties have limited its clinical use. Thus, this compound has usually worked as a tool medicine to

2

investigate the potential therapeutic utility of PDE2 inhibitors. The inhibition of PDE2A by 4

3

enhanced the long-term potentiation of synaptic transmission without altering basal synaptic

4

transmission. In addition, 4 improved memory performance in social and object recognition memory

5

tasks and rescued deficits of spontaneous alternation in the T-maze induced by the

6

N-methyl-D-aspartate (NMDA) antagonist MK801.31 Further study of object location and

7

recognition tasks indicated that its role in memory improvement was probably due to the

8

enhancement of memory consolidation instead of attention.32 In memory-impaired, aged rats, 4

9

enhanced the impaired learning and recognition memory for objects at different ages and was

10

accompanied by increased basal constitutive nitric oxide synthase activity in the hippocampus and

11

striatum.33 Another study discovered that the inhibition of PDE2 in the hydrolysis of both cGMP and

12

cAMP using 4 improved spatial object memory consolidation in both early and late stages, whereas

13

the vardenafil-induced inhibition of PDE5 in the hydrolysis of cGMP only enhanced the early stage,

14

and the rolipram-induced inhibition of PDE4 in the hydrolysis of cAMP enhanced only the late

15

stage.34 In APP/PS1 mice, chronic treatment with 4 improved memory performance without causing

16

anxiety, indicating that signaling pathways other than the NO/cAMP/CREB pathway might be

17

responsible for its cognition-enhancing effects.35 Most recently, another study demonstrated that 4

18

reduced stress-induced activation of an extracellularly regulated protein kinase and attenuated the

19

loss

20

neuroplasticity-related NMDAR-CaMKII-cGMP/cAMP signaling pathway.36

of

stress-induced

transcription

factors

and

plasticity-related

proteins

via

the

21

Pharmaceutical study in rats revealed that the brain penetration of BAY 60-7550 was poor. The

22

administration of BAY 60-7550 at the dose of 10 mg/kg only resulted in a brain concentration of 3.6

23

ng/g.37 Thus, the main reason for the good memory improvement effects obtained by BAY 60-7550 ACS Paragon Plus Environment 16

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1

is probably due to the highest expression of PDE2 in brain, in where low brain concentrations of

2

PDE2 inhibitor might be sufficient to active the cAMP and cGMP signal, causing signal

3

amplification for memory improvement.

4

ND-7001 (5), developed by the Neuro3d company, showed an IC50 of 50 nM against PDE2 and

5

good selectivity over PDE3 and PDE4 (Figure 3).38 Its safety, tolerability, and pharmacokinetics

6

were evaluated in Phase I trials, which demonstrated that it was safe and well tolerated at high doses

7

and produced no sedation, memory disturbance or withdrawal effects.39 However, no further

8

development has been reported since 2010.

9

PF-999 (6, also named as PF-05180999), developed by Pfizer, showed remarkable inhibitory

10

activity against PDE2 (IC50: 2.3 nM) and selectivity over other PDEs, as well as a reasonable free

11

brain/plasma ratio in rats (Figure 3).40 PF-999 was found to increase the level of cGMP in the

12

cerebrospinal fluid of rats, attenuate ketamine-induced memory deficits and reverse spatial learning

13

and memory in scopolamine-induced models.39 In 2015, a study that explored the primarily

14

presynaptic mechanism of PDE2A inhibition was also performed by using PF-999. The results

15

showed that the inhibition of PDE2 might be involved in short-term synaptic plasticity by

16

modulating the hydrolysis of cAMP to accommodate changes in cGMP levels associated with

17

presynaptic short-term plasticity.41 Currently, 6 has already completed two Phase I clinical trials: one

18

trial evaluated its safety, tolerability, and pharmacokinetics in healthy subjects, and the other

19

evaluated the relative bioavailability of a modified-release formulation at 30 mg and 120 mg in

20

patients with schizophrenia.42-44 However, no further information has been reported since 2012.

21

Recently, compound 71 (7), developed by Pfizer, showed an IC50 of 2 nM against PDE2 and

22

selectivity of up to 4000-fold over other PDEs (Figure 3).45 7 increased the level of cGMP in rodent

23

brain regions expressing the highest levels of the PDE2A enzyme. In the radial arm maze, 7 ACS Paragon Plus Environment 17


1

significantly attenuated memory impairments induced by ketamine in rats. Furthermore, 7 reversed a

2

maximum of 80% of the MK-801-induced local field potential disruption at a steady-state Cbu of 11

3

nM. These results indicated selective PDE2A inhibition in brain-potentiated, pharmacologically

4

induced NMDA hypofunction in vivo and that it is suitable to be used in treating neurological and

5

neuropsychiatric disorders associated with NMDA hypofunction, such as schizophrenia.

6

TAK-915, developed by Takeda with no structural or other information disclosed, has already

7

finished two phase I clinical trials of healthy participants in 2015. One trial served to examine the

8

degree and duration of brain PDE2A enzyme occupancy/target engagement after its administration in

9

order to provide evidence of dosing and a schedule for future clinical studies of schizophrenia.46 The

10

other trial was conducted to characterize its safety, tolerability, and plasma pharmacokinetic

11

properties when administered as single and multiple oral suspension doses at escalating dose levels

12

in healthy participants, including elderly participants.47

13 14

2.3 PDE3 inhibitors

15

Similar to PDE1 and PDE2, PDE3 is another subfamily responsible for hydrolyzing both cAMP

16

and cGMP and has two isoforms: PDE3A and PDE3B. In the brain, the expression of PDE3A and

17

PDE3B is relatively low and is mainly in the cerebellum. In the periphery, the expression of PDE3A

18

is mainly in the heart, while the expression of PDE3B is mostly in the lungs and liver (Figure S3).18

19

PDE3A variants have differential expression in cardiovascular tissues. In intracellular, PDE3B is

20

predominantly membrane-associated and localized to endoplasmic reticulum and microsomal

21

fractions. Furthermore, although the concentration of PDE3 is low in brain compared with other PDE

22

subfamilies, the inhibition of PDE3 might be sufficient to active the cAMP and cGMP signal,

23

causing signal amplification for memory improvement.8, 48 ACS Paragon Plus Environment 18

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1

AD and vascular dementia are two major types of dementia in elderly persons. A number of

2

elderly people may suffer from both conditions. Cerebral white matter lesions have been

3

demonstrated to be one important risk factor for transforming mild cognitive impairment to AD and

4

are the main reason for the age-dependent coexistence of AD and cerebrovascular disease.49, 50 The

5

neurovascular dysfunction of aged AD is associated with cerebral ischemia and the accumulation of

6

Aβ.51, 52

7

8 9

Figure 4. Selective PDE3 inhibitor, cilostazol, may be used to treat cerebrovascular diseases and AD

10

Cilostazol (8) is a selective PDE3 inhibitor (IC50: 0.2 µM) that has been clinically used as an

11

antiplatelet drug for the prevention of cerebrovascular disease (Figure 4).53 Recently, therapy using 8

12

directed at both vascular and neurodegenerative aspects of dementia has been considered a more

13

suitable approach for elderly patients with AD. In an Aβ25-35-injected mouse model of AD, repeated

14

administration of 8 significantly attenuated impairment of spontaneous alternation and reversed the

15

shortening of step-down latency induced by Aβ25-35. The increased level of MDA was completely

16

prevented, indicating that 8 may reverse oxidative damage induced by Aβ25-35.54 Another study

17

demonstrated that 8 significantly attenuated Aβ accumulation and improved spatial learning and

18

memory. The level of Apolipoprotein E (ApoE), a protein associated with Alzheimer's

19

neurofibrillary tangles and Aβ protein, was decreased, resulting in reduced Aβ aggregation.55

20

A clinical study of 10 patients with moderate AD proved that 8 ameliorated cognitive decline ACS Paragon Plus Environment 19


Page 20 of 61

1

efficiently when co-administered with donepezil after an average follow-up period. However, this

2

combinatorial therapy had no effect on patients with moderate or severe dementia.56,

3

retrospective analysis revealed that 8 could significantly improve memory in patients with mild

4

cognitive impairment, but no significant effect was observed in patients with normal cognitive

5

function or dementia.58 The clinical effects of monotherapy with galantamine or 8 added to

6

combinatorial therapy in AD patients were also evaluated in a clinical study. Galantamine or 8

7

monotherapy increased the cognitive, affective, and activities of daily living functions in AD patients,

8

while the combination of galantamine and 8 resulted in a better therapeutic effect than the

9

monotherapy.59 Most recently, a clinical study was performed in a large Asian population to

10

investigate the potential risk and benefit of using 8 to reduce the risk of dementia (9148 participants

11

free of dementia at 40 years or older). Patients given 8 had a significantly decreased risk of incident

12

dementia compared with patients without the drug. Notably, the use of 8 had a dose-dependent

13

association with the reduced rate of dementia emergence. Subgroup analysis identified a decrease in

14

dementia in 8 users with diagnosed ischemic heart disease and cerebrovascular disease.60

57

A

15

Two clinical trials of 8 related to AD or dementia were registered on the clinicaltrials.gov. A

16

Phase IV study was performed by Seoul National University Hospital in 2011 to examine the added

17

effect of 8 with donepezil treatment using cognitive tasks and PET imaging in mild to moderate AD

18

patients with subcortical white matter hyperintensities (WMHI).61 A Phase II trial in patients with

19

mild cognitive impairment was performed by the National Cerebral and Cardiovascular Center in

20

2015 to evaluate whether 8 could prevent the conversion from mild cognitive impairment to

21

dementia.62

22 23

2.4 PDE4 inhibitors ACS Paragon Plus Environment 20

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1

PDE4 is a subfamily that hydrolyzes cAMP only. The four isoforms of PDE4 (PDE4A, PDE4B,

2

PDE4C, and PDE4D) are widely expressed in the CNS and have been found to remain present in the

3

aged and Alzheimer’s brain.63 PDE4B is highly expressed in most areas of brain, except in the dorsal

4

root ganglia, where the levels of all the PDE4 isoforms are low. The levels of PDE4A and PDE4B

5

are equally high in the cortex, but PDE4A is two- to four-fold lower in other brain regions. PDE4C

6

has very low expression in the brain. PDE4D has relatively high expression in the frontal cortex but

7

is 3- to 10-fold lower than PDE4B in all CNS tissues. In the periphery, PDE4B and PDE4D are two

8

major isoforms (Figure S4).18

9

Currently, three PDE4 inhibitors, namely, roflumilast, crisaborole, and apremilast, have been

10

approved on the market for the treatment of chronic obstructive pulmonary disease (COPD), atopic

11

dermatitis, and psoriatic arthritis, respectively.64 In general, PDE4 inhibitors have been widely

12

explored for the treatment of AD.65 However, most of the current PDE4 inhibitors may cause emetic

13

side effects, limiting their usage in CNS diseases.



1 2 3


4 5

Rolipram (9) is the first generation of PDE4 inhibitors with an IC50 of 230 nM (Figure 5).

6

Compared with the approved drugs roflumilast and apremilast, rolipram has good brain penetration,

7

or an ability to pass the blood-brain barrier. The concentration of 9 in the brain is twice as high as that

8

in the plasma.65 However, low-dose administration of rolipram causes emesis. Currently, rolipram is

9

widely used to investigate the underlying mechanisms of PDE4 inhibitors in AD.

10

The neuroprotective effect of rolipram in AD models was first demonstrated on

11

hippocampal-dependent memory tasks in 1998, which suggested that the inhibition of PDE4 might

12

decrease the threshold for generating long-lasting long-term potentiation (LTP) and increase ACS Paragon Plus Environment 22

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1

behavioral memory through the cAMP pathway.16 Gong and coworkers demonstrated that 9

2

improved cognitive deficits in both LTP and contextual learning in APP/PS1 mouse models. Notably,

3

its effect on the improvement of LTP and basal synaptic transmission, as well as working, reference,

4

and associative memory deficits, lasts at least two months after treatment.66 The loss of dendritic

5

spines and dystrophic neurites existed in the hippocampus of APP/PS1 transgenic mice and AD

6

patients. Gong also demonstrated that 9 reversed spine density to a normal level in APP/PS1 mice

7

and aged mice. The changes in dendritic structure and function caused by Aβ peptides were also

8

reversed by rolipram.67 In Aβ25–35- or Aβ1-40-injected rats, chronic administration or repeated

9

treatment with 9 reversed memory impairment, while acute treatment with 9 did not. Furthermore,

10

the decreased levels of Pcreb and Bcl-2 and the increased level of NF-κB p65 and Bax in the

11

hippocampus were regulated by 9 in a dose-dependent manner.68 These results indicated that the

12

attenuation of neuronal inflammation and apoptosis mediated by cAMP/CREB signaling might be

13

involved in the process, which is in accordance with a previous study showing that 9 reversed

14

scopolamine-induced and time-dependent memory in object recognition tasks by elevating cAMP

15

levels.69,70 Most recently, it has been proven that 10 significantly improved learning and memory

16

ability in streptozotocin-induced and naturally aged mice.71 Its potential for treatment of memory

17

dysfunctions can probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative, and

18

anti-inflammatory actions and other effects.72, 73

19

Roflumilast (10, Daliresp or Daxas) was the first selective PDE4 inhibitor approved by the FDA

20

for the treatment of COPD in 2011 (Figure 5). Compared with 9, 10 showed a significantly better

21

inhibitory affinity against PDE4 with decreased emetic properties and may be suitable as a candidate

22

drug for the treatment of AD.74 A preclinical study demonstrated that both 10 and 9 have positive

23

effects on memory improvement in an object location task in male C57BL/6NCrl mice. In the ACS Paragon Plus Environment 23


1

Y-maze test, 11 improved spatial memory performance, while 9 did not. More importantly, 10

2

produced emetic-like effects at a dose 100 times that of the memory-enhancing dose, indicating that

3

it is relatively safe in AD treatment. A single administration of donepezil or 10 did not improve

4

memory, while combining efficacious doses of both fully reversed scopolamine-induced memory

5

deficits in object recognition tasks.75 Its beneficial effect on memory and its non-emetic properties

6

promoted 10 to clinical trials of AD. Currently, 10 has already finished one Phase II study as a

7

translational cognition enhancer76 and one Phase I study to evaluate whether co-administration of 10

8

and donepezil could attenuate scopolamine-induced cognitive impairment.77 A preclinical trial is

9

underway to evaluate its effect on preventing the onset of AD in high-risk individuals.78 Although

10

the IC50 of 11 is almost 1000 times higher than that of 9 in vitro, the effects obtained in memory

11

improvement experiments by roflumilast are almost the same or even less than those of rolipram.

12

The difference has been attributed to the relatively poor ability of roflumilast to penetrate the

13

blood-brain barrier. Recent studies demonstrated that 10 efficiently reversed cognitive impairment

14

induced by hypertension in rodents, even at low doses.79,80

15

HT-0712 (11) was developed as a novel PDE4 inhibitor by Bourtchouladze and Scott (Figure 5).

16

Both 11 and 9 ameliorated long-term memory in a mouse model of Rubinstein-Taybi syndrome.81,82

17

Currently, 11 has already completed a Phase II trial to evaluate its efficacy in improving memory and

18

cognitive performance in subjects with age-associated memory impairment (AAMI) and had positive

19

results.83

20

MK-0952 (12), developed by Merck, shows an IC50 of 0.6 nM against PDE4 (Figure 5).84 A

21

Phase II clinical trial with 12 was performed to determine its effect on improving cognitive

22

impairments in patients in mild to moderate stages of AD.85

23

Etazolate (13, also named as EHT0202) is a PDE4 inhibitor and a GABA-A receptor ACS Paragon Plus Environment 24

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1

modulator (Figure 5).86 Its underlying mechanism of memory improvement in AD might be

2

cross-linked.87 Currently, 13 has already finished one Phase II trial to evaluate its safety and

3

tolerability as an adjunctive therapy to acetylcholinesterase inhibitors in mild to moderate AD.88 The

4

results showed that 13 was safe and generally well tolerated. Dose-dependent numbers of early

5

withdrawal and central nervous system-related adverse events were observed.89

6

FFPM (14) is a novel PDE4 inhibitor that was developed by Ke and coworkers and that has an

7

IC50 of 26 nM and good selectivity over other PDEs (Figure 5).90 Its effects on learning and memory

8

were investigated by Xu and coworkers using the APP/PS1 mouse model of AD.91 After 3 weeks of

9

treatment, the learning and memory abilities of APP/PS1 transgenic mice were significantly

10

improved, as measured by the Morris water maze test and the step-down passive avoidance task. 14

11

had no significant effect on the duration of xylazine/ketamine anesthesia in mice, indicating that 14

12

might not cause emesis during the treatment of AD. Furthermore, 14 penetrated the blood-brain

13

barrier quickly after oral administration, with a half-life in plasma of 1.5 h.

14

PDE4D has been demonstrated to be the main subtype involved in the process of memory

15

consolidation and LTP. The inhibition of PDE4 by 9 in PDE4D-deficient mice did not alter memory

16

performance.92 Thus, selective PDE4D inhibitors may have beneficial effects on cognition

17

enhancement. However, the inhibition of PDE4D is also the main reason for the emetic side effects

18

of a PDE4 inhibitor, as it may mimic the pharmacological actions of α2-adrenoceptor antagonists.93,

19

94

20

GEBR-7b (15) is a selective PDE4D inhibitor, showing low inhibitory activities towards

21

PDE4A4, PDE4B2, and PDE4C2 (Figure 5).95 An in vivo study demonstrated that 16 improved

22

spatial and object recognition memory in late-phase consolidation processes in object recognition

23

and location tests. The level of cAMP in the hippocampus was increased without affecting the level ACS Paragon Plus Environment 25


1

of Aβ. The effect of 15 on memory was 3- to 10-fold more potent than that of 9. In the

2

xylazine/ketamine test, no emetic effect was observed in mice, even at doses of 30 times higher than

3

those in the object location test for behavioral performance improvement. The greatly reduced emetic

4

effect of 15 is probably due to the relatively low doses required to improve memory.96 Most recently,

5

the development of 15 led to a new molecule, 8a (16), which showed good PDE4D3 selective

6

inhibition and the ability to cross the blood-brain barrier.97 The brain/plasma ratio of 16 is 0.8,

7

while those of roflumilast and rolipram are approximately 1 and 2, respectively. In the object

8

recognition task, administration of 16 at a dose of 0.003 mg/kg significantly enhanced long-term

9

memory performance and fully reversed the scopolamine induced short-term memory deficit

10

without causing any emetic-like behavior. These results offered another strategy for the discovery

11

of PDE4 inhibitors with non-emesis behavior for the treatment of AD.

12

Recent studies demonstrated that allosteric modulators of PDE4D that do not completely inhibit

13

enzymatic activity may enhance memory with reduced emetic effects. Unlike the usual PDE4

14

inhibitors, these PDE4D allosteric modulators form an allosteric binding to the specific

15

phenylalanine in primates in the UCR2 region of PDE4D, resulting in its high affinity and selectivity.

16

In the scopolamine-impaired mouse model, the PDE4D allosteric modulator D159687 (17), with an

17

IC50 of 27 nM against PDE4D and good selectivity, efficiently improved cognitive memory in novel

18

object recognition and Y-maze tests (Figure 5). Compared with 9, 17 showed 100-fold less emetic in

19

S. murinus, 3,000-fold less in the beagle dog, and 500-fold less in monkey. Thus, 17 may work

20

efficiently to improve memory with reduced emetic potential. The total brain/plasma AUC ratio for

21

D159687 was above 1 across both rodents and primates.98

22

Another PDE4D allosteric modulator, BPN14770 (18), had IC50 values of 8 and 130 nM against

23

human and mouse PDE4D, respectively (Figure 5). This modulator also enhanced the long-term ACS Paragon Plus Environment 26

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1

potential in hippocampal slices.99 In 2016, two clinical trials of 18 were conducted for the evaluation

2

of its safety, tolerability, and pharmacokinetic profile in different subjects.100, 101 Another Phase I

3

trial to assess its effect on reversing scopolamine-induced cognitive impairment in healthy volunteers

4

is in progress, with donepezil used as the positive control.102

5 6


7 8

2.5 PDE5 inhibitors

9

Phosphodiesterase-5 (PDE5) is a subfamily that hydrolyzes cGMP and has one isoform, PDE5A.

10

Compared with other PDE subfamilies, the expression of PDE5A in the brain is relatively low. The

11

levels of PDE5A mRNA are highest in the periphery, bladder, and lungs (Figure S5).18 However,

12

several studies have demonstrated that PDE5 inhibitors have a potential therapeutic effect on the

13

treatment of AD through stimulation of nitric oxide (NO)/cGMP signaling by elevating the level of

14

cGMP. Currently, several PDE5 inhibitors, such as sildenafil and tadalafil, have been approved by

15

the FDA for the treatment of erectile dysfunction and pulmonary arterial hypertension.103

16

Sildenafil (19) has shown an IC50 of 2.2 nM against PDE5A and moderate selectivity across

17

other PDEs (Figure 6).104 Its pharmaceutical properties, such as easily crossing the blood brain

18

barrier and lower toxicity, indicate that 19 is suitable as a candidate drug for the investigation of the ACS Paragon Plus Environment 27


1

effect and mechanism of PDE5 inhibitors in neurodegenerative processes.104-109 19 produced an

2

immediate and long-lasting improvement of synaptic function, CREB phosphorylation, and memory

3

in an APP/PS1 mouse model.105 In the same study, PDE5 inhibitor tadalafil and a highly selective

4

PDE1 inhibitor IC354 (IC50: 80 nM) were also tested. Tadalafil (1 mg/kg, i.p.) did not improve either

5

contextual fear conditioning or spatial working memory in APP/PS1 mice and IC354 had no effect

6

on the LTP amplitude in hippocampal slices. Further study proved that 19 regulates the level of Aβ

7

possibly by modifying their production, metabolism, or clearance. The increased CREB

8

phosphorylation might be due to the anti-inflammatory effect of 19 via the cGMP/PKG/pCREB

9

signaling pathway.106 Currently, 19 has already finished one Phase IV trial for schizophrenia and one

10

Phase IV trial for Parkinson's disease.110,111 However, the clinical trial for AD has not been

11

performed yet. It is worth mentioning that the selectivity of 19 for PDE1 and PDE6 is 180 and 12,

12

respectively, and may cause mild vasodilatory effects and transiently disturb vision.

13

As is mentioned before, there are direct links between AD pathology with cerebrovascular

14

disease. Compared to healthy controls, patients with AD usually have reduced cerebral blood flow

15

(CBF), increased cerebrovascular resistance, and reduced cerebral metabolic rate. A clinical study on

16

AD patients was performed in 2017, demonstrating that 19 could significantly improve the cerebral

17

blood flow and oxygen consumption at a single dose of 50 mg. The cerebrovascular reactivity was

18

decreased. This result indicated that the memory effect of PDE5 inhibitors may possibly be due to

19

the increase in cerebral blood flow mediated by PDE5 expressed in endothelial brain tissue.112

20

Tadalafil (20) is an efficient PDE5 inhibitor developed by Eli Lilly (Figure 6). Compared

21

with 19, 20 has shown better selectivity against PDE6 and a longer half-life.113 These properties

22

suggest that 20 might be more suitable than 19 as an anti-AD drug. However, the administration

23

of 20 (1 mg/kg, i.p.) did not improve either contextual fear conditioning or spatial working ACS Paragon Plus Environment 28

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1

memory in APP/PS1 mice, while 19 did.105 The main reason for this result has been attributed to

2

the fact that 19 can cross the BBB, while 20 cannot. A further study in 2013 proved that 12% of

3

tadalafil found in the bloodstream crosses the BBB and reaches the brain. Chronic treatment with

4

20 leads its accumulation in the brain of the J20 transgenic mouse model of AD, which reverses

5

memory deficits. 20 is even more effective than 19 in the improvement of memory performance. The

6

level of hyperphosphorylated Tau protein decreased via activation of the pAkt/GSK3 pathway.

7

Neither 20 nor 19 decreased the level of Aβ plaques, indicating that cognition enhancement by

8

PDE5 inhibitors may occur without gross improvement of Aβ pathology.114 Currently, a phase II

9

clinical trial of tadalafil is underway in patients with cerebral small vessel disease, to identify

10

whether tadalafil improves blood flow in deep brain tissue and potentially improves cognitive

11

function 115

12

A quinoline compound, 7a (21), exhibited a higher inhibitory affinity (IC50 = 0.27 nM) and

13

better selectivity than 19, vardenafil, and 20 (Figure 6). In the APP/PS1 mouse model of AD, 21

14

crossed the blood brain barrier readily and increased the level of cGMP in the mouse hippocampus,

15

thus restoring synaptic plasticity and memory damage caused by the elevation of Aβ42.116

16

The pathogenic mechanism of AD is complicated. A combination of multiple targets involved

17

in AD has been considered more appropriate than individual ones. Histone deacetylase inhibitors

18

(HDACIs) are potential modulators of cognitive impairment in AD. Administration of both the

19

pan-HDACI vorinostat and PDE5 inhibitor 20 in aged Tg2576 mice effectively reversed the

20

cognitive deficits and increased the reduced dendritic spine density in hippocampal neurons. The

21

co-administration of these two drugs gave better and longer-lasting effects than each drug alone.117

22

Based on this result, CM-414 (22), an inhibitor acting on both PDE5 and HDAC was developed with

23

remarkable IC50 values against PDE5 and moderate inhibition against HDAC class I (Figure 6).118 22 ACS Paragon Plus Environment 29


1

was able to cross the blood-brain barrier, inducing AcH3K9 acetylation and CREB phosphorylation

2

in the hippocampus and rescuing LTP in APP/PS1 mice. Chronic treatment of Tg2576 mice with 22

3

decreased the level of Aβ and tau phosphorylation in the brain and increased the inactive form of

4

GSK3β. Both the decrease in dendritic spine density in hippocampal neurons and the cognitive

5

deficits were reversed. Thus, 22 may act as an efficient PDE5/HDAC dual inhibitor with a good

6

safety profile, and it may be worth exploration in the clinical trials for AD patients.119 O N N H

S

23 (S14)

7 8

IC50 (PDE7A): 4.7 M IC50 (PDE7B): 8.8 M MW:254.3

Figure 7. Current PDE7 inhibitor for the treatment of AD.

9 10

2.6 PDE7 inhibitors

11

PDE7 is a cAMP-specific subfamily composed of two isoforms, PDE7A and PDE7B.

12

Compared with other PDEs, the expression of PDE7 is relatively low in all tissues. The expression of

13

PDE7B is relatively higher than that of PDE7A in the CNS, such as in the caudate, nucleus

14

accumbens, cortical tissues, and hippocampus. In the periphery, the level of PDE7A is higher than or

15

equal to that of PDE7B in the heart, lungs, etc. (Figure S6).18 Moreover, in situ hybridization

16

demonstrated that the expression of PDE7B remained unchanged and that PDE7A was reduced in the

17

hippocampal regions of advanced AD patients.120 Several PDE7 inhibitors have been recently

18

reported to be potential new agents for the treatment of brain diseases. However, investigation of

19

PDE7 inhibitors for the treatment of AD is still limited.121

20

A quinazoline compound, S14 (23), was identified by the CODES program with IC50 values of ACS Paragon Plus Environment 30

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1

4.7 and 8.8 µM against PDE7A and PDE7B, respectively, as well as good selectivity over the other

2

five PDEs (Figure 7).122,123 In the APP/PS1 mouse, its administration reduced behavioral impairment

3

in the T-maze via the cAMP/CREB signaling pathway. Moreover, 23 reduced the accumulation of

4

Aβ deposits and modulated brain astrocyte distribution. Significant decreases in tau phosphorylation,

5

cell death and proapoptotic protein expression were also observed.124

6

7 8


9 10

2.7 PDE9 inhibitors

11

PDE9 is a subfamily that hydrolyzes cGMP only. Among the 11 PDE subfamilies, PDE9 has

12

the highest binding affinity for cGMP (Km: 70 nM) with only isoform PDE9A.125 The expression of

13

PDE9A occurs in most human tissues (Figure S8). In the CNS, the highest levels of PDE9A is in the

14

caudate nucleus and cerebellum. In the periphery, the highest level of PDE9 occurs in the bladder.

15

PDE9 has been regarded as an important target since several efficient inhibitors are in clinical trials

16

for the treatment of AD. ACS Paragon Plus Environment 31


1

In 2005, the first selective PDE9 inhibitor, BAY 73-6691 (24), was reported by Bayer. 24

2

showed an IC50 of 55 nM against PDE9A and moderate selectivity over PDE1 (Figure 8).126 A

3

program was performed to investigate its potential treatment effect on neurological diseases,

4

including AD, but was terminated in 2004 with no reason disclosed. Currently, 24 is often used as a

5

tool in medicine to investigate the underlying mechanism of PDE9A inhibition in AD.127-130 24

6

enhanced the ability of acquisition, consolidation, and retention of LTP in social and object

7

recognition tasks in rodents, improving the scopolamine-induced passive avoidance deficit and the

8

MK-801-induced short-term memory deficits.127 Compared with donepezil, which only increased

9

early LTP, 24 improved both early and late LTP, even transforming early into late LTP. These

10

results indicated that PDE9 inhibition might have better therapeutic effects on AD patients than

11

donepezil.128 In APP transgenic Tg2576 mice with Alzheimer’s plaque pathology, 24 restored Aβ42

12

oligomer-induced LTP and improved memory performance.129,130

13

PF-04447943 (25) is a highly selective and brain penetrant PDE9A inhibitor that was developed

14

by Pfizer in 2011, with an IC50 of 8.3 nM against PDE9A and above 100-fold selectivity over other

15

PDEs (Figure 8).131 Compared with other current AD drugs, which only ameliorate learning and

16

memory function, 25 was able to reverse scopolamine-induced deficits in both the Morris water

17

maze and novel object recognition tests.132 In the Y-maze spatial recognition memory, social

18

recognition memory and scopolamine-deficit novel object recognition tasks, 25 significantly

19

improved cognitive performance.133 In the Tg2576 mouse model of amyloid precursor protein (APP)

20

overexpression, 25 regulated the dendritic spine density of hippocampal neurons.134A preclinical test

21

proved that 25 has excellent tolerability, exposure, and a long half-life of 19-31 h. Currently, 25 has

22

already completed six Phase I trials and one Phase II trial for AD. In the six Phase I trials, its safety,

23

tolerability, and blood level after multiple doses were evaluated in different subjects with good ACS Paragon Plus Environment 32

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1

results. One Phase I trial was performed to evaluate its safety when given in combination with

2

donepezil in AD patients and to evaluate the absorption and distribution of both it and donepezil.135

3

Its efficacy, safety, and pharmacokinetics were investigated in a phase II trial in subjects with mild to

4

moderate probable AD.136 However, its administration over two weeks did not improve cognitive

5

behavior or cause global changes with statistically significant differences compared with a placebo.

6

BI-409306 was developed by Boehringer Ingelheim for the treatment of cognitive disorder

7

diseases, such as AD and schizophrenia (IC50: 52 nM). Currently, BI-409306 has already

8

completed fifteen Phase I trials. The safety, tolerability, and pharmacokinetics of BI-409306

9

were investigated in different subjects, including healthy males, CYP2C19-genotyped persons,

10

and patients with AD. The results showed that BI-409306 was safe and well tolerated in most

11

subjects. The most commonly experienced adverse effects were headache and photopsia, with

12

mild to moderate intensity, which might be caused by the modulation of PDE9A of some

13

processes in the retina. Furthermore, in a study aiming to assess its exposure in cerebrospinal

14

fluid, BI-409306 was found to cross the blood-CSF barrier and be rapidly absorbed in plasma

15

and distributed in CSF. The level of cGMP in CSF increased in a dose-dependent manner.

16

Currently, two phase II trials for AD are in progress.137,138 One trial aims to investigate its effect

17

on cognitive impairment in AD patients in comparison with a placebo or donepezil. The other

18

trial aims to explore the effect of different doses on the treatment of AD. IMR-687(26) and

19

PF-4181366, developed by H Lundbeck company and Pfizer, respectively were evaluated in

20

preclinical and clinical trials of AD, but no progress has been reported.

21

A series of PDE9 inhibitors was reported by Luo’s group with the assistance of structure-based

22

design and computational docking (Figure 8).139 Compound 27 has an IC50 of 21 nM against

23

PDE9A and >150-fold selectivity over other PDEs. Further structural modification of compound 27 ACS Paragon Plus Environment 33


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1

led to compound 3r (28), with an improved IC50 of 0.6 nM. However, these two compounds were

2

designed for the treatment of diabetes, and thus, their physicochemical properties might be beyond

3

the range of CNS drugs.140 Compound C33 (29), with an IC50 value of 16 nM against PDE9 and

4

moderate selectivity over other PDEs, could significantly improve memory and cognitive impairment

5

induced by scopolamine or Aβ25-35.141 In 2015, Luo’s group used a combinatorial method to discover

6

novel PDE9 inhibitors with new scaffolds rather than pyrazolopyrimidinones from the SPECS

7

database.142 Fifteen hits out of 29 molecules, with five novel scaffolds, were identified as PDE9

8

inhibitors. Further structural modification of compound AG-690/40135604 (IC50 = 8.0 µM) led to a

9

new compound, 30, with an improved inhibitory affinity of 2.1 µM. The five novel scaffolds

10

discovered could be used for the rational design of PDE9 inhibitors with higher affinities. N N

F N

OMe

O Me

N

O

N Me O

N N

N

N

H N

OMe

N

O

Br OMe

N

11 12

31 (PF-02545920) IC50 (PDE10A): 0.37 nM MW:392.5

N N 32 (TAK-063) IC50 (PDE10A): 0.3 nM MW:428.4

33 (OMS-824) IC50 (PDE10A): not disclosed MW:487.1

Figure 9. Current PDE10 inhibitors for the treatment of AD and other diseases.

13 14

2.8 PDE10 inhibitors

15

PDE10A is a dual-specificity subfamily that hydrolyzes cAMP (Km = 0.05 µM) and cGMP (Km

16

= 3 µM).143 The highest expression of PDE10A in the brain is in the caudate nucleus, and it is also

17

the most prevalent PDE species in this tissue, together with PDE1B. The level of PDE10A is

18

relatively high in the nucleus accumbens. In other parts of the brain and the peripheral tissues

19

examined, the level of PDE10 mRNA could be detected but was very low (Figure S8).18 Furthermore, ACS Paragon Plus Environment 34

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1

the level of PDE10A decreased in the striatum of patients with Huntington's disease and immediately

2

preceded the onset of motor symptoms.144 Currently, PDE10 is considered a promising target for

3

CNS diseases, especially for schizophrenia and Huntington's disease.

4

PF-02545920 (31, MP-10) was developed by Pfizer (Figure 9).145 After its safety, tolerability,

5

and pharmacokinetics in different subjects were identified in five Phase I trials, its efficacy in the

6

treatment of schizophrenia was evaluated in three Phase II trials. However, 31 failed to reach its

7

primary efficacy end-point in a trial with schizophrenia patients in 2012, and thus, its condition was

8

changed to Huntington’s disease, which was completed in 2014.146 Another Phase II trial in 2015

9

sought to investigate its long-term safety, tolerability, and efficacy in subjects with Huntington's

10

disease. However, this study was terminated in 2016 due to no significant difference being observed

11

in the primary endpoint between 31 and placebo.147

12

TAK-063 (32), developed by Takeda by using structure-based drug design (SBDD) techniques,

13

has an IC50 of 0.30 nM against PDE10 (Figure 9). Its selectivity over other PDEs could be up to

14

15000-fold. Its pharmacokinetics were promising, including high brain penetration in mice.148 In vivo

15

studies have demonstrated that 32 produced dose-dependent, antipsychotic-like effects in

16

METH-induced hyperactivity and prepulse inhibition in rodents.149 Furthermore, 32 attenuated both

17

phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced

18

working memory deficits in an eight-arm radial maze task in rats.150 Recently, 32 has been evaluated

19

in a Phase II trial for the treatment of acutely exacerbated schizophrenia.151

20

OMS-824 (33, OMS643762), developed by Omeros Corporation, has finished one Phase II trial

21

that evaluated its safety, tolerability, and pharmacokinetics in psychiatrically stable schizophrenia

22

patients (Figure 9).152 Another Phase I trial of 33 in subjects with Huntington's disease has been

23

suspended with no reason disclosed.153 Another PDE10 inhibitor, EVP-6308, has finished a Phase II ACS Paragon Plus Environment 35


1

trial in subjects with schizophrenia who are on a stable anti-psychotic regimen.154

2 3

3. Other PDE subfamilies and their application.

4

PDE6 is an enzyme-specific hydrolyzing cGMP that is divided into three subtypes: PDE6A, 6B

5

and 6C. The retina is the only human tissue with high levels of PDE6A expression. PDE6 has not

6

been detected in the CNS.18 Currently, the purification of PDE6 enzyme is still a challenge, and no

7

selective PDE6 inhibitor has been reported yet.155 The structural, biochemical, and pharmacologic

8

properties of PDE6 are closely related to PDE5. PDE5 inhibitors, such as sildenafil, vardenafil, and

9

tadalafil, have exhibited low selectivity towards PDE6, which may disturb the cGMP signaling

10

pathway in the retina during treatment for other diseases and may cause side effects, including visual

11

disturbances, blurry vision, and light sensitivity.156

12

PDE8 specifically hydrolyzes cAMP, which is coded by two genes: PDE8A and PDE8B.

13

PDE8A exists throughout the brain and peripheral organs at low levels, while PDE8B is mainly

14

expressed in the brain and thyroid.18 Based on its expression, PDE8 has been considered a target for

15

the treatment of thyroid dysfunction and modulation of steroidogenesis in the testes and adrenal

16

glands.157-159 Furthermore, the overexpression of PDE8B, as well as PDE7, has been observed in the

17

brains of Alzheimer’s patients, indicating that the inhibition of PDE8B was able to enhance memory

18

function by the activation of the cAMP signal pathway. However, only a few PDE8-selective

19

inhibitors are available,160 limiting the usage of PDE8.

20

PDE11A is the only isoform of PDE11 that hydrolyzes both cAMP and cGMP. PDE11A is

21

expressed at relatively low levels in most tissues, especially in the cortex and the hippocampus.18

22

Studies of PDE11 are few, and the biological roles of PDE11 are poorly understood due to the lack

23

of selective inhibitors. ACS Paragon Plus Environment 36

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1


4. Prospective

2

In light of the recent high-profile Phase III failures of several Aβ-targeting agents, such as

3

bapineuzumab and solanuzumab, there has been a trend to refocus on the discovery of novel

4

non-Aβ-directed, anti-AD drugs rather than acetylcholine inhibitors and NMDA antagonists, which

5

still has a long way to go.

6

Over the last twenty decades, great efforts have been made to understand the roles of PDEs and

7

to discover effective inhibitors for cognitive improvement in AD. Compared with other hot research

8

areas related to the deposition of Aβ or aggregation of Tau protein, PDE inhibitors hydrolyse two

9

important second messengers (cAMP/cGMP), which can be used before the formation of amyloid

10

plaques and neurofibrillary tangles, regulating central nervous system function such as

11

emotion-related learning, memory, and neural regeneration. Alterations in the levels of cAMP and

12

cGMP are due to the accumulation of cyclase and the degradation of PDE regulation. The regulation

13

of the concentration of cAMP/cGMP may cause a makes PDEs promising drug targets. Until now,

14

there have been many reports of PDE inhibitors with outstanding and remarkable effects on memory

15

in AD in preclinical (Table 2) or clinical (Table 3) trials. The role of PDE inhibitors in improving

16

learning and memory is gaining more and more data, but the underlying mechanisms are still not

17

fully understood. Sufficient evidence has demonstrated that the cAMP-mediated PKA/CREB or

18

cGMP-mediated PKG/CREB signaling pathways are involved in this process. In addition, enhanced

19

cAMP/cGMP concentrations by several PDE inhibitors can significantly improve both early and late

20

LTP, even transforming early into late LTP, which demonstrates that the inhibition of PDEs might

21

have better therapeutic effects on AD patients than acetylcholine inhibitors and suggests a possible

22

mechanism for the use of PDE inhibitors in the treatment of AD. This finding may lead to the

23

development of drugs for treating cognitive dysfunctions, especially in AD.

24

As candidates for the treatment of AD, PDE inhibitors may cause several adverse reactions,

25

which greatly limits their clinical applications. For example, most current PDE4 inhibitor including

26

Roflumilast may cause nausea, emesis, diarrhea, and headache, due to the inhibition of PDE4D ACS Paragon Plus Environment 37


1

subtype. PDE5 inhibitor Sildenafil may cause visual abnormality as it inhibit PDE6 at the same time.

2

Solutions for avoiding these side effects should be further studied through effective methods. Many

3

studies used structure-based molecular design methods to discover highly selective PDE inhibitors.

4

In addition, the discovery of novel allosteric modulators93-97 based on the allosteric site of PDEs

5

could significantly improve their selectivity and decrease the likelihood of side effects. Such

6

allosteric modulators will provide a better basis for the development of future anti-AD drugs in the

7

field of PDE inhibitors, but their role needs to be examined in further preclinical or clinical

8

evaluations.

9 10

■ ASSOCIATED CONTENT

11

Supporting Information

12

The Supporting Information is available free of charge on the ACS Publications website.

13 14

■ AUTHOR INFORMATION

15

Corresponding Authors

16

* E-mail: [email protected]; Fax: +86-20-3994 3000 (H.B.L.).

17

ORCID

18

Yinuo Wu: 0000-0003-3071-5333

19

Hai-Bin Luo: 0000-0002-2163-0509

20 21

Funding

22

This work was supported by the National Key R&D Program of China (2017YFB0202600), Natural

23

Science Foundation of China (21402243, 21572279, 81522041, 81373258, and 81602968), Science

24

Foundation of Guangdong Province (2014A020210009 and 2016A030310144), Guangdong


Page 38 of 61

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1

Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2016), and

2

Foundation of Traditional Chinese medicine Bureau of Guangdong Province (20171049).

3 4

Notes

5

The authors declare no competing financial interest.

6 7

Biographies

8

Yinuo WU is currently an assistant professor in the School of Pharmaceutical Science at Sun Yat-sen

9

University (SYSU). She received her PhD degree at SYSU in 2011 and subsequently went to Hong

10

Kong Polytechnic University as a postdoctoral fellow. Her research encompasses discovery of novel

11

PDEs inhibitors and their applications in the treatment of neurological disorders.

12

Zhe LI is currently an assistant professor in the School of Pharmaceutical Science at Sun Yat-sen

13

University (SYSU). He received his PhD degree in Medicinal Chemistry from SYSU in 2017.

14

During his PhD study, he went to Prof. Chang-Guo Zhan’s group as an exchange student in

15

University of Kentucky for two years. His research in Medicinal Chemistry focuses on the

16

development of drug design methods and the applications of these methods in the development of

17

novel PDEs inhibitors.

18

Yi-You HUANG is currently pursuing his Ph.D in the School of Pharmaceutical Science at Sun

19

Yat-sen University under the supervision of Prof. Hai-Bin Luo. He went to Prof. Hengming Ke’s

20

group as a visiting scholar in the University of North Carolina at Chapel Hill from 2017.04 to

21

2017.10. His research focuses in structural biology and their applications on the design of novel PDE

22

inhibitors.

23

Deyan WU is currently an assistant professor in the School of Pharmaceutical Science at Sun

24

Yat-sen University (SYSU). He received her PhD degree at East China University of Science &

25

Technology in 2014 and subsequently worked in ChemPartner as a senior researcher. After one-year

26

research, he joined Sun Yat-sen University as an assistant professor. His research currently ACS Paragon Plus Environment 39


Page 40 of 61

1

specialized in medicinal chemistry and total synthesis of natural products, focusing on the research

2

and development of PDEs inhibitors for Treatment of Pulmonary Arterial Hypertension (PAH),

3

erectile dysfunction (ED), chronic obstructive pulmonary disease (COPD), and structural

4

modification of active natural products as novel PDEs inhibitors.

5

Hai-Bin LUO is currently a full professor and the associate dean of the School of Pharmaceutical

6

Science at Sun Yat-sen University (SYSU). He received his bachelor degree from Xiamen university

7

in 1999 and PhD degree from Hong Kong Baptist university in 2005. After one-year postdoctoral

8

research, he joined Sun Yat-sen University as an associate professor. His research currently

9

encompasses the rational design and discovery of novel PDEs inhibitors and their applications in the

10

treatment of several diseases.

11 12

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1 2

Figure captions

3

Figure 1: The relation of PDE inhibition and the cAMP or cGMP signaling pathway in the

4

brain. PDE: phosphodiesterase; AC: adenyl cyclase; GC: guanylyl cyclase; ATP: adenosine

5

triphosphate; GTP: guanosine triphosphate; PKA: protein kinase A; PKG: protein kinase G;

6

P: phosphorylated; CREB: cAMP response element binding protein.

7


8

Figure 3. Current PDE2 inhibitors for the treatment of AD

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Figure 4. Selective PDE3 inhibitor, cilostazol, may be used to treat cerebrovascular diseases

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and AD

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Figure 7. Current PDE7 inhibitor for the treatment of AD.

14


15

Figure 9. Current PDE10 inhibitors for the treatment of AD and other diseases.

16 17


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Table of Contents Graphic

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Novel Phosphodiesterase Inhibitors for Cognitive Improvement in

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