Development and application of high throughput plasma stability assay for drug discovery

Di, Li; Kerns, Edward H.; Hong, Yan; Hong, Chen

doi:10.1016/j.ijpharm.2005.03.022

Cited by 161 publications

(139 citation statements)

References 21 publications

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“…Unstable compounds tend to exhibit rapid clearance, short halflives and consequently poor in vivo activity (Di et al, 2005). Compounds with certain functional groups including amides, esters, lactams, sulfonamides, have a tendency to undergo hydrolysis by plasma enzymes.…”

Section: Discussionmentioning

confidence: 99%

In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors

Konsoula

Jung

2008

International Journal of Pharmaceutics

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Histone deacetylase inhibitors (HDACIs) are emerging as a new class of therapeutic agents with potent antitumor activities in a broad spectrum of human cancers. In this study, the in vitro plasma stability, permeability, solubility, and lipophilicity (logD) of two mercaptoacetamide-based HDACIs (coded as W2 and S2) were evaluated and compared to Vorinostat (SAHA). The results demonstrated that the compounds manifested high solubility in HCl (pH 1.2) but lower in PBS (pH 7.4) than SAHA. Moreover, mercaptoacetamide-based HDACIs exhibited higher lipophilicity values compared to SAHA. The permeability of these compounds was evaluated using the Caco-2 cell monolayer as a model of the intestinal mucosa. The Caco-2 studies revealed that the compounds S2 and W2 are highly permeable with apparent permeability coefficients (P app ) in the apical to basolateral direction of 7.33 × 10 −6 and 15.0 × 10 −6 cm/s, respectively. The in vitro stability was determined in human, mouse, porcine and rat plasma. Data showed that the compound W2 is more stable in human and rat plasma and the S2 is more stable in all plasma species than SAHA. Taken together, these results indicate that the mercaptoacetamide-based HDACIs possess favorable solubility, lipophilicity, permeability and plasma stability features.

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Section: Discussionmentioning

confidence: 99%

In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors

Konsoula

Jung

2008

International Journal of Pharmaceutics

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“…To achieve a more metabolically stable Fer-1 analog, we created an imine-type structure (SRS15-72A) that showed high stability in microsomes with a half-life of t 1/2 = 154 min (Table S2). This metabolically stable analog turned out not to be sufficiently stable in the plasma due to its ethyl ester moiety (Table S3), a functional group well-known to be more susceptible to hydrolysis in plasma (31). Because a previous study showed that the ethyl ester is important to maintain the potency of Fer-1, we aimed at improving the plasma stability, while maintaining high microsomal stability by creating additional imine analogs with isopropyl (SRS16-80) and tert-butyl (SRS16-86) esters (Fig.…”

Section: Generation Of a Third-generation Ferrostatin With Increasedmentioning

confidence: 99%

Synchronized renal tubular cell death involves ferroptosis

Linkermann

Skouta

Himmerkus

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

910

804

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Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, irondependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the firstin-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.

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“…The data obtained were plotted as natural logarithm (ln) of the remaining percentages of Boc5 versus incubation time (Lallemand et al 2005). The in vitro plasma half life (t 1/2 , h) at certain incubation times was calculated from the slope of the linear regression of the natural logarithm of the parent remaining percentage versus incubation time using the following equation (Konsoula and Jung, 2008;Di et al, 2005). The final half-lives (t 1/2 ) expressed as the mean from multiple incubation time points with standard deviations.…”

Section: In Vitro Plasma Stability and Albumin Stabilitymentioning

confidence: 99%

The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism

Ge¹,

Ai²,

Hu³

et al. 2013

European Journal of Pharmaceutical Sciences

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Development and application of high throughput plasma stability assay for drug discovery

Cited by 161 publications

References 21 publications

In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors

In vitro plasma stability, permeability and solubility of mercaptoacetamide histone deacetylase inhibitors

Synchronized renal tubular cell death involves ferroptosis

The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism

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