Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment

Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually. ARTICLE HISTORY

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“…[34,38,39]). The PDE4 inhibitor MK-0952 was given to patients with mild to moderate AD [77]. However, the results were never disclosed.…”

Section: Resultsmentioning

confidence: 99%

“…MK-0952 (Merck) [77], was investigated in a Phase II study in patients with mild to moderate AD and completed in 2008, but no results were ever disclosed (ClinicalTrials.gov Identifier: NCT00362024). Whether MK-0952 is emetic is not known.…”

Section: Mk-0952mentioning

confidence: 99%

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

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

153

168

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“…Among the several groups tested, the cyclopropane carboxylic acid moiety in 125 was the best as it had low potency in the HWB assay and an improved oral bioavailability compared to 124 as shown in Figure 52. 163 antihypertensive β-blockers that (a) would be more potent than available β-blockers, (b) showed increased β 1 adrenoceptor selectivity, and (c) possessed a desirable PK profile, including excellent oral absorption, low first pass metabolism, and a plasma half life >12 hours, that will permit once-a-day dosing. Since compound 129 (metoprolol) was known to be a cardioselective β 1 -adrenoceptor blocker, it was considered to be a good starting point for SAR studies.…”

Section: Bradykinin B1 Receptor Antagonist 120mentioning

confidence: 98%

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

2016

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Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,

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“…For instance, MK-0952 was tested on cognitive impairment in mild to moderate Alzheimer's disease (ClinicalTrials.gov, NCT00362014). However, its announced results [24] have not been disclosed. Currently, HT-0712 is being tested on age-associated memory impairment (ClinicalTrials.gov, NCT02013310).…”

Section: Introductionmentioning

confidence: 99%

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses

Vanmierlo

Creemers

Akkerman

et al. 2016

Behavioural Brain Research

100

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Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

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Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment

Cited by 38 publications

References 31 publications

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

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

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses

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