Drug-like Properties and ADME of Xanthone Derivatives: The Antechamber of Clinical Trials
- 4 November 2016
- journal article
- review article
- Published by Bentham Science Publishers Ltd. in Current Medicinal Chemistry
- Vol. 23 (32), 3654-3686
- https://doi.org/10.2174/0929867323666160425113058
Abstract
Xanthone derivatives have been described as compounds with a privileged scaffold exhibiting diverse biological/pharmacological activities, what directed the interest to pursue the development of these derivatives into drug candidates. Nevertheless, to achieve this purpose it is crucial to study their pharmacokinetics and toxicity (PK/tox) properties as decision endpoints to continue or interrupt the development investment. This review aims to expose the most relevant analytical methods used in the physicochemical and PK/tox studies in order to detect, quantify, and identify different bioactive xanthones. Analyzing the main results from in vitro and in vivo systems towards ADME properties such as solubility, lipophilicity, pKa, chemical and metabolic stability, permeability, transporters modulation, and plasma protein binding, it is possible to uncover some threats governing the PK properties and to understand the bioavailability and drugability of xanthone derivatives. The last section of this review focuses on a case-study of the development of the drug candidate DMXAA, which has reached clinical trials, to provide the paths and the importance of PK/tox parameters of this scaffold. The data assembled in this review intends to guide for tackling issues in the design of potential lead compounds and drug candidates with a xanthone scaffold.Keywords
This publication has 119 references indexed in Scilit:
- Biological Activities and Bioavailability of Mangosteen Xanthones: A Critical Review of the Current EvidenceNutrients, 2013
- Induction of expression and functional activity of P-glycoprotein efflux transporter by bioactive plant natural productsFood and Chemical Toxicology, 2011
- The anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces IFN-β-mediated antiviral activity in vitro and in vivoJournal of Leukocyte Biology, 2010
- Temporal aspects of the action of ASA404 (vadimezan; DMXAA)Expert Opinion on Investigational Drugs, 2010
- The development of the tumor vascular-disrupting agent ASA404 (vadimezan, DMXAA): current status and future opportunitiesExpert Opinion on Investigational Drugs, 2010
- The Vascular Disrupting Agent 5,6‐Dimethylxanthenone‐4‐Acetic Acid Improves the Antitumor Efficacy and Shortens Treatment Time Associated with Photochlor‐sensitized Photodynamic Therapy In VivoPhotochemistry and Photobiology, 2009
- Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancerBritish Journal of Cancer, 2008
- Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug DiscoveryThe AAPS Journal, 2008
- The chemotherapeutic agent DMXAA potently and specifically activates the TBK1–IRF-3 signaling axisThe Journal of Experimental Medicine, 2007
- Rat Tumor Response to the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid as Measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging, Plasma 5-Hydroxyindoleacetic Acid Levels, and Tumor NecrosisNeoplasia, 2006