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Pharmacokinetic, pharmacodynamic and metabolic characterization of a brain retentive microtubule (MT)-stabilizing triazolopyrimidine.

ABSTRACT: Previous studies revealed that examples of the non-naturally occurring microtubule (MT)-stabilizing triazolopyrimidines are both brain penetrant and orally bioavailable, indicating that this class of compounds may be potentially attractive in the development of MT-stabilizing therapies for the central nervous system (CNS). We now report on the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of a selected triazolopyrimidine congener, (S)-3-(4-(5-chloro-7-((1,1,1-trifluoropropan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)-propan-1-ol (4). These studies revealed that 4 exhibits longer brain than plasma half-life that may be exploited to achieve a selective accumulation of the compound within the CNS. Furthermore, compound metabolism studies suggest that in plasma 4 is rapidly oxidized at the terminal hydroxyl group to form a comparatively inactive carboxylic acid metabolite. Peripheral administration of relatively low doses of 4 to normal mice was found to produce a significant elevation in acetylated α-tubulin, a marker of stable MTs, in the brain. Collectively, these results indicate that 4 may effectively target brain MTs at doses that produce minimal peripheral exposure.

SUBMITTER: Cornec AS

PROVIDER: S-EPMC4569539 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Pharmacokinetic, pharmacodynamic and metabolic characterization of a brain retentive microtubule (MT)-stabilizing triazolopyrimidine.

Cornec Anne-Sophie AS James Michael J MJ Kovalevich Jane J Trojanowski John Q JQ Lee Virginia M-Y VM Smith Amos B AB Ballatore Carlo C Brunden Kurt R KR

Bioorganic & medicinal chemistry letters 20150314 21

Previous studies revealed that examples of the non-naturally occurring microtubule (MT)-stabilizing triazolopyrimidines are both brain penetrant and orally bioavailable, indicating that this class of compounds may be potentially attractive in the development of MT-stabilizing therapies for the central nervous system (CNS). We now report on the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of a selected triazolopyrimidine congener, (S)-3-(4-(5-chloro-7-((1,1,1-trifluoropropan-2-yl) ...[more]

PMID: 25819095

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Project description:IntroductionCariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.MethodsIn vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR.ResultsSimilar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.ConclusionOverall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.

Project description:BackgroundAlzheimer's disease (AD) and related tauopathies are neurodegenerative diseases that are characterized by the presence of insoluble inclusions of the protein tau within brain neurons and often glia. Tau is normally found associated with axonal microtubules (MTs) in the brain, and in tauopathies this MT binding is diminished due to tau hyperphosphorylation. As MTs play a critical role in the movement of cellular constituents within neurons via axonal transport, it is likely that the dissociation of tau from MTs alters MT structure and axonal transport, and there is evidence of this in tauopathy mouse models as well as in AD brain. We previously demonstrated that different natural products which stabilize MTs by interacting with β-tubulin at the taxane binding site provide significant benefit in transgenic mouse models of tauopathy. More recently, we have reported on a series of MT-stabilizing triazolopyrimidines (TPDs), which interact with β-tubulin at the vinblastine binding site, that exhibit favorable properties including brain penetration and oral bioavailability. Here, we have examined a prototype TPD example, CNDR-51657, in a secondary prevention study utilizing aged tau transgenic mice.Methods9-Month old female PS19 mice with a low amount of existing tau pathology received twice-weekly administration of vehicle, or 3 or 10 mg/kg of CNDR-51657, for 3 months. Mice were examined in the Barnes maze at the end of the dosing period, and brain tissue and optic nerves were examined immunohistochemically or biochemically for changes in MT density, axonal dystrophy, and tau pathology. Mice were also assessed for changes in organ weights and blood cell numbers.ResultsCNDR-51657 caused a significant amelioration of the MT deficit and axonal dystrophy observed in vehicle-treated aged PS19 mice. Moreover, PS19 mice receiving CNDR-51657 had significantly lower tau pathology, with a trend toward improved Barnes maze performance. Importantly, no adverse effects were observed in the compound-treated mice, including no change in white blood cell counts as is often observed in cancer patients receiving high doses of MT-stabilizing drugs.ConclusionsA brain-penetrant MT-stabilizing TPD can safely correct MT and axonal deficits in an established mouse model of tauopathy, resulting in reduced tau pathology.

Dataset Information

Pharmacokinetic, pharmacodynamic and metabolic characterization of a brain retentive microtubule (MT)-stabilizing triazolopyrimidine.

Publications

Pharmacokinetic, pharmacodynamic and metabolic characterization of a brain retentive microtubule (MT)-stabilizing triazolopyrimidine.

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