Water-soluble prodrugs of an Aurora kinase inhibitor

Oslob, Johan D.; Heumann, Stacey A.; Yu, Chul H.; Allen, Darin; Baskaran, Sundarababu; Bui, Minna; Delarosa, Erlie; Fung, Amy; Hashash, Ahmad; Hau, Jonathan; Ivy, Sheryl; Jacobs, J. W.; Lew, Willard; Maung, Jack; McDowell, Robert S.; Ritchie, Sean C.; Romanowski, M.J.; Silverman, Jeffrey A.; Yang, Wenjin; Zhong, Min; Fuchs-Knotts, Tarra

doi:10.1016/j.bmcl.2009.01.043

Cited by 21 publications

(10 citation statements)

References 22 publications

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“…Various N-(acyloxy)methylene-substituted prodrugs, some with basic substituents, as well as a (phosphonooxy)methyl prodrug were prepared. The latter was superior in terms of water solubility, chemical stability, and pharmacokinetic properties resulting in high blood levels of the parent drug [17]. It was found that the bis-choline salt had an about twofold higher water solubility than the disodium or the dipotassium salt.…”

Section: Prodrug Approaches For Enhancingmentioning

confidence: 97%

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Prodrug Approaches for Enhancing the Bioavailability of Drugs with Low Solubility

Müller

2009

Chemistry & Biodiversity

120

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Low water solubility and low bioavailability are frequent problems in drug development, particularly in the area of central nervous system (CNS) drugs. This short review describes selected prodrug approaches which have been developed to enhance the bioavailability of drugs, especially that of poorly soluble drugs. Some of the most successful drugs on the market are prodrugs. With a better understanding of active-transport processes at cell membranes in the gut as well as at the blood-brain barrier, the importance of prodrug approaches will further increase in the future. Prodrug approaches will already be considered in the early phase of drug discovery.

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Section: Prodrug Approaches For Enhancingmentioning

confidence: 97%

“…In a recent study, the poor water solubility of the anti-cancer drug SNS-314 was to be increased by a prodrug approach [17]. SNS-314 is an aurora kinase inhibitor, which is currently evaluated in clinical trials in patients with advanced solid tumors (Fig.…”

Section: Prodrug Approaches For Enhancingmentioning

confidence: 99%

Prodrug Approaches for Enhancing the Bioavailability of Drugs with Low Solubility

Müller

2009

Chemistry & Biodiversity

120

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“…Several examples in the literature highlight medicinal chemistry efforts to improve solubility, via introduction of ionizable, N-containing basic groups [7,13,14], or disruption of planar crystal structure [15,16], as is shown in Fig. 1 Prodrug approaches have also been used to improve solubility of drugs such as that shown in Fig.…”

Section: Solubility and Dissolutionmentioning

confidence: 99%

“…But before a significant amount of effort is dedicated to optimize and modulate drug metabolism and pharmacokinetics (DMPK) properties of a new chemotype, it is very important to evaluate the ability of the in vitro ADME assays to predict the in vivo situation, that is, establish in vitro -in vivo correlations (IVIVCs) at very early stages of drug discovery. The following are some underlying reasons that are being made in predicting Cl hep from Cl int for the failure of IVIVCs [7]: 16. Inaccurate determination of f m × f m, CYP (in the case of CYP-mediated DDI).…”

Section: Failure Of In Vitro -In Vivo Correlation For Prediction Of Ddismentioning

confidence: 99%

ADMEProfiling in Drug Discovery and Development: An Overview

Bohnert

Prakash

2012

Encyclopedia of Drug Metabolism and Interactions

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The applications of parallel synthesis and combinatory chemistry to expedite lead finding and lead optimization processes have shifted the chemical libraries toward poorer biopharmaceutical, ADME (absorption, distribution, metabolism, and excretion), and pharmacokinetic (PK) properties. A drug candidate should have desirable biopharmaceutical properties such as good solubility and good permeability, as well as optimal and ADME/PK properties. The early knowledge of liability of biopharmaceutical, ADME/PK, and DDI properties is very valuable in drug candidate selection process. In the last one decade, multiple in silico, in vitro, and in vivo ADME studies have been developed and implemented in the drug discovery and development process to alert chemists and drug metabolism scientists of the potential ADME, PK and DDI issues in the clinic. In this chapter, we attempt to discuss these various ADME profiling approaches in drug discovery and development process and the latest technologies of the selected assays.

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“…Cyclodextrins form noncovalent dynamic inclusion complexes with a wide variety of compounds in solution, resulting in an increase in solubility. The most common type of cyclodextrin complexes is the 1:1 drug/cyclodextrin complex, where one drug molecule forms a complex with one cyclodextrin molecule (Oslob et al, 2009). The total solubility of the drug in solution is the sum of the solubility of the drug itself and the amount of complex formed.…”

Section: Incorporation Of Complex Agentsmentioning

confidence: 99%