Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain

Hirose, Ryo; Manabe, Haruhiko; Nonaka, Hiromi; Yanagawa, Koji; Akuta, Kaori; Sato, Soichiro; Ohshima, Etsuo; Ichimura, Michio

doi:10.1016/j.ejphar.2007.06.045

Cited by 28 publications

(14 citation statements)

References 28 publications

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“…We did, however, identify some subtle differences in the kinetics of binding to the HARBS, in that GSK356278 dissociated faster than rolipram. It is thought that binding to the HARBS is the molecular mechanism that drives emesis (Hirose et al, 2007) as opposed to inhibition of cAMP hydrolysis, and, whereas it is not known why binding to the HARBS is responsible for inducing emesis or other behavioral side effects, it is possible that the kinetics of this binding may contribute to side effects for a given level of occupancy at the enzyme for a particular inhibitor, and perhaps the faster rate of dissociation for GSK356278 contributes to the improved therapeutic index over rolipram. We have not yet carried out a systematic comparison of other inhibitors to prove or disprove this concept, and this will be the focus for future experiments.…”

Section: Discussionmentioning

confidence: 99%

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

Rutter

Poffe

Cavallini

et al. 2014

J Pharmacol Exp Ther

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Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe doselimiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo [3,4-b] pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC 50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC 50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was .150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was .10 versus ,1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.

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Section: Discussionmentioning

confidence: 99%

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

Rutter

Poffe

Cavallini

et al. 2014

J Pharmacol Exp Ther

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“…Emesis induced by PDE4 inhibitors was reported to be related to the degree of PDE4 inhibition based on the ex vivo evaluation of [ 3 H]rolipram binding in the brain although roflumilast was not included in the study [30]. Although species difference is needed to consider, the present study may suggest that 30-40 % of in vivo brain PDE4 occupancy, which corresponds to clinical dose of roflumilast, might be an acceptable level of PDE4 inhibition not to induce severe nausea and emesis if the in vivo brain target occupancy can be used as an objective parameter.…”

Section: Discussionmentioning

confidence: 99%

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

Takano

Garcia‐Segovia

et al. 2018

Mol Imaging Biol

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Purpose: Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates. Procedures: Positron emission tomography (PET) measurements with (R)-[11 C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (V T ) and V T /fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy.Results: The brain uptake of (R)-[ 11 C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose-and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/ kg of roflumilast, regardless of outcome measures, V T or V T /fp. Conclusions: This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates.Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects.

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“…Emetic potential was investigated further in Suncus murinus (Asian house shrew), the beagle dog and cynomolgus monkey. Suncus have an emetic response to motion, ethanol overdose, and many classes of drugs that are emetic in human (Ueno et al 1987;Hirose et al 2007). A UCR2-directed, full inhibitor with >100-fold selectivity for PDE4D over PDE4B (D157140) caused emesis at 0.1 mg/kg, indicating that potent PDE4D inhibitors are emetic (Robichaud et al 2002b).…”

Section: Active Site-directed Competitive Inhibitors Bind An Open Pdementioning

confidence: 98%

“…The No Observable Effect Level (NOEL) for emesis was the maximum dose at which no effect on emesis was observed. Rolipram data in Suncus are from (Hirose et al 2007), rolipram data in dog are from (Heaslip and Evans 1995), and the rolipram emetic threshold in the cynomolgus monkey is projected based on allometric scaling from human (Hebenstreit et al 1989) (Bailey et al 1996). CREB regulates a transcriptional cascade ultimately leading to the remodeling of synaptic structure (Tully et al 2003).…”

Section: Active Site-directed Competitive Inhibitors Bind An Open Pdementioning

confidence: 99%

Small Molecule Allosteric Modulators of Phosphodiesterase 4

Gurney

Burgin²,

Magnússon

et al. 2011

Phosphodiesterases as Drug Targets

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Phosphodiesterase 4 (PDE4) inhibitors have shown benefit in human clinical trials but dosing is limited by tolerability, particularly because of emesis. Novel cocrystal structures of PDE4 catalytic units with their regulatory domains together with bound inhibitors have revealed three different PDE4 conformers that can be exploited in the design of novel therapeutic agents. The first is an open conformer, which has been employed in the traditional approach to the design of competitive PDE4 inhibitors. The second is an asymmetric dimer in which a UCR2 regulatory helix from one monomer is placed in a closed conformation over the opposite active site in the PDE4 dimer (trans-capping). Only one active site can be closed by an inhibitor at a time with the consequence that compounds exploiting this conformer only partially inhibit PDE4 enzymatic activity while retaining potency in cellular and in vivo models. By placing an intrinsic ceiling on the magnitude of PDE4 inhibition, such compounds may better maintain spatial and temporal patterning of signaling in cAMP microdomains with consequent improved tolerability. The third is a symmetric PDE4 conformer in which helices from the C-terminal portion of the catalytic unit cap both active sites (cis-capping). We propose that dual-gating of PDE4 activity may be further fine tuned by accessory proteins that recognize open or closed conformers of PDE4 regulatory helices.

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Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain

Cited by 28 publications

References 28 publications

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

Small Molecule Allosteric Modulators of Phosphodiesterase 4

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