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Molecules 2009, 14(10), 4231-4245; doi:10.3390/molecules14104231

Soft Alkyl Ether Prodrugs of a Model Phenolic Drug: The Effect of Incorporation of Ethyleneoxy Groups on Transdermal Delivery

1
Laboratory of Medicinal Chemistry, NCI, NIH, NCI – Frederick, Frederick, MD 21702, USA
2
Laboratory of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
3
Department of Medicinal Chemistry, University of Florida, P.O. Box 100485, Gainesville, FL 32610, USA
*
Author to whom correspondence should be addressed.
Received: 18 September 2009 / Revised: 13 October 2009 / Accepted: 19 October 2009 / Published: 22 October 2009
(This article belongs to the Special Issue Prodrugs)
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Abstract

Two different types of soft alkyl ether prodrugs incorporating ethyleneoxy groups into the promoiety have been synthesized for a model phenol (acetaminophen, APAP): alkyloxycarbonyloxymethyl type (AOCOM) and N-alkyl-N-alkyloxycarbonyl-aminomethyl type (NANAOCAM). The solubilities in isopropyl myristate, SIPM, and water, SAQ, partition coefficients between IPM and pH 4.0 buffer, KIPM:4.0, and the delivery of total species containing APAP through hairless mouse skin from IPM, JMMIPM, have been measured for the prodrugs. The JMMIPM values were accurately predicted by the Roberts-Sloan (RS) equation. Only modest increases in JMMIPM were realized (about 1.4 times) by each type. The only prodrug that was more water soluble and more lipid soluble than APAP did not improve JMMIPM of APAP. This result may be due to the strong association of water molecules with the ethyleneoxy groups, and especially the triethyleneoxy derivative, which dramatically increases the molecular weight and depresses JMMIPM.
Keywords: topical delivery; Roberts-Sloan equation; water solubility; lipid solubility; prodrugs topical delivery; Roberts-Sloan equation; water solubility; lipid solubility; prodrugs
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Thomas, J.D.; Majumdar, S.; Sloan, K.B. Soft Alkyl Ether Prodrugs of a Model Phenolic Drug: The Effect of Incorporation of Ethyleneoxy Groups on Transdermal Delivery. Molecules 2009, 14, 4231-4245.

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