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Molecules 2014, 19(10), 16381-16401;

Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives

Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, Romania
Author to whom correspondence should be addressed.
Received: 29 August 2014 / Revised: 26 September 2014 / Accepted: 29 September 2014 / Published: 13 October 2014
(This article belongs to the Section Medicinal Chemistry)
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Several new pyrazole derivatives have demonstrated promising antiproliferative and cytotoxic effects, but their poor solubility raised concerns over possible biopharmaceutical limitations. In order to improve their pharmaceutical potential we performed the biopharmaceutical profiling for nine pyrazole compounds using in vitro and computational methods. The experimental solubility was determined in five different media using a validated HPLC method. Although the experimental solubility was lower than the predicted one, a good linear relationship was observed. The results also indicated a minimal impact of endogenous tensioactives on solubility, suggesting dissolution rate limited absorption. The in silico experiments were focused on identification of molecular determinants of solubility, evaluation of drug-likeness, prediction of in vivo absorption based on mechanistic models, as well as identification of the main factors that could impact on the oral bioavailability. The results suggested that dose, solubility and particle size are the main determinants of absorption, whereas permeability has little effect, confirming the BCS Class II behavior of the compounds. The present investigation was able to rank the tested compounds in terms of biopharmaceutical behavior, and indicated the B3 series compounds as having a more favorable absorption profile making them the main candidates for advance to the pre-clinical in vivo studies. View Full-Text
Keywords: acylthiourea; pyrazole derivatives; solubility; FaSSIF; FeSSIF; ADME prediction acylthiourea; pyrazole derivatives; solubility; FaSSIF; FeSSIF; ADME prediction

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Anuta, V.; Nitulescu, G.M.; Dinu-Pîrvu, C.E.; Olaru, O.T. Biopharmaceutical Profiling of New Antitumor Pyrazole Derivatives. Molecules 2014, 19, 16381-16401.

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