Assessing the issue of instability due to Michael adduct formation in novel chemical entities possessing a carbon-carbon double bond during early drug development- applicability of common laboratory analytical protocols
| العنوان: | Assessing the issue of instability due to Michael adduct formation in novel chemical entities possessing a carbon-carbon double bond during early drug development- applicability of common laboratory analytical protocols |
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| المؤلفون: | Ravikanth Bhamidipati, Rao N. V. S. Mamidi, Akshanth Reddy Polepally, Ramesh Mullangi, Shaik Abdul Naveed, Venkata V. Pavan Kumar, Nuggehally R. Srinivas, N. Selvakumar, Jagannath Kota, Karnati Harinder Reddy |
| المصدر: | Biomedical Chromatography. 22:960-976 |
| بيانات النشر: | Wiley, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Pharmacology, chemistry.chemical_classification, Spectrometry, Mass, Electrospray Ionization, Chromatography, Double bond, Chemistry, Clinical Biochemistry, General Medicine, Biochemistry, Combinatorial chemistry, Carbonyl group, Carbon, Xenobiotics, Analytical Chemistry, Adduct, chemistry.chemical_compound, Nucleophile, Drug development, Drug Discovery, Organic chemistry, Reactivity (chemistry), Molecular Biology, Chromatography, Liquid |
| الوصف: | The discovery of small-molecule novel chemical entities (NCEs) is often a complex play between appropriate structural requirements and optimization of the desired efficacy, safety and pharmacokinetic properties. One of the typical structural variants such as having an active carbon–carbon double bond (α, β-unsaturated carbonyl group) in xenobiotics may lead to stability issues. Such functionalities are extremely reactive, paving way to nucleophilic attack by endogenously occurring and ubiquitous nucleophiles like thiols. While it is easy to make a unilateral decision to not pursue the development of xenobiotics with such functionalities, we question the wisdom of such a decision. In this report, we present in vitro methodologies with appropriate examples to illustrate the ease of assessing the reactivity of the xenobiotics containing double bonds with a known nucleophile. The protocols involve simple reaction procedures followed by measurements using standard laboratory equipments (UV spectrophotometer, HPLC and LC-MS). Our data suggests that not all xenobiotics with carbon–carbon double bonds readily form a Michael's adduct product with glutathione. Hence, the criterion for dropping discovery compounds because of α,β-unsaturated double bonds needs to be reconsidered. Copyright © 2008 John Wiley & Sons, Ltd. |
| تدمد: | 1099-0801 0269-3879 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0cc5c5f1783c95e21ce31b98a55e104e https://doi.org/10.1002/bmc.1015 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....0cc5c5f1783c95e21ce31b98a55e104e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10990801 02693879 |
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