Stability Challenges in Drug Discovery

Di, Li; Kerns, Edward H.

doi:10.1002/cbdv.200900061

Cited by 27 publications

(19 citation statements)

References 43 publications

(49 reference statements)

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“…It is known that the stability of simvastatin decreases with increasing temperature whereas sufficient stability has been reported in a pH range of 3 to 6. (Álvarez-Lueje et al, 2005); (Di and Kerns, 2009) All samples were immediately diluted 1/100 in a stabilization mixture (pH 3.5), consisting of MeOH:0.02N HCl (50:50) containing 400 µM of the esterase inhibitor bis-4-nitrophenylphosphate. The stability of the ester prodrug was confirmed in this stabilization mixture.…”

Section: Stabilization Mixturementioning

confidence: 99%

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

Geboers

Stappaerts

Tack³

et al. 2016

International Journal of Pharmaceutics

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Simvastatin (SV) is marketed as a lactone ester prodrug which is hydrolyzed to the active simvastatin hydroxyacid (SVA). SV is characterized by a low solubility and undergoes extensive first-pass metabolism. In this study, the influence of the upper gastrointestinal environment on the intraluminal behavior of simvastatin was investigated by a series of in vitro experiments. Dissolution, stability and two-stage dissolution tests were performed using simulated and human gastrointestinal fluids. The dissolution studies revealed a relatively slow dissolution of SV as well as conversion of SV to SVA. The hydrolysis of SV was further examined and stability studies indicated a faster conversion in gastric fluids than in intestinal fluids. These isolated phenomena were then confirmed by the more integrative two-stage dissolution studies. To estimate the predictive value of the in vitro tests, an additional in vivo study was performed in which the gastrointestinal concentration-time profiles also revealed a slow dissolution of SV and faster degradation of SV to SVA in the stomach than in the intestinal tract. However, the plasma concentrations of SV and SVA did not directly correlate with the observed gastrointestinal concentrations, suggesting that gut wall and hepatic metabolism have a greater impact on systemic exposure of SV than the intraluminal interconversion between SV and SVA.

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Section: Stabilization Mixturementioning

confidence: 99%

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

Geboers

Stappaerts

Tack³

et al. 2016

International Journal of Pharmaceutics

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“…An important part of preformulation constitutes studies of drug–excipient interactions, where the potential degradation of an active pharmaceutical ingredient (API) in combination with excipients is investigated . Excipients are usually selected from the GRAS (Generally Recognized As Safe) list and generally considered to be biologically inactive.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of the Esterification of Active Pharmaceutical Ingredients Containing Carboxylic Acid Functionality in Polyethylene Glycol: Formulation Implications

Schou-Pedersen

Hansen

Moesgaard

et al. 2014

Journal of Pharmaceutical Sciences

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“…34 Previously, we and others reported classes of compounds that were not stable to assay conditions. 16,35 One class, p -hydroxyarylsulfonamides, decomposed to form a reactive intermediate (likely a quinone) capable of forming covalent adducts with biological thiols including protein cysteines residues.…”

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confidence: 99%

Post-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2 H -pyrrol-2-one actives verified by ALARM NMR

Dahlin

Nissink

Francis

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Despite its wide use, not every high-throughput screen (HTS) yields chemical matter suitable for drug development campaigns, and seldom are ‘go/no-go’ decisions in drug discovery described in detail. This case report describes the follow-up of a 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one active from a cell-free HTS to identify small-molecule inhibitors of Rtt109-catalyzed histone acetylation. While this compound and structural analogs inhibited Rtt109-catalyzed histone acetylation in vitro, further work on this series was halted after several risk mitigation strategies were performed. Compounds with this chemotype had a poor structure–activity relationship, exhibited poor selectivity among other histone acetyltransferases, and tested positive in a β-lactamase counter-screen for chemical aggregates. Furthermore, ALARM NMR demonstrated compounds with this chemotype grossly perturbed the conformation of the La protein. In retrospect, this chemotype was flagged as a ‘frequent hitter’ in an analysis of a large corporate screening deck, yet similar compounds have been published as screening actives or chemical probes versus unrelated biological targets. This report—including the decision-making process behind the ‘no-go’ decision—should be informative for groups engaged in post-HTS triage and highlight the importance of considering physicochemical properties in early drug discovery.

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Stability Challenges in Drug Discovery

Cited by 27 publications

References 43 publications

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

Kinetics of the Esterification of Active Pharmaceutical Ingredients Containing Carboxylic Acid Functionality in Polyethylene Glycol: Formulation Implications

Post-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2 H -pyrrol-2-one actives verified by ALARM NMR

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