Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties.
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Over B, McCarren P, Artursson P, Foley M, Giordanetto F, Grönberg G, Hilgendorf C, Lee MD, Matsson P, Muncipinto G, Pellisson M, Perry MWD, Svensson R, Duvall JR, Kihlberg J
J. Med. Chem. 57 (6) 2746-2754 [2014-03-27; online 2014-02-15]
Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH→NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure-property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's rule of 5.
Chemical Biology Consortium Sweden (CBCS) [Collaborative]
PubMed 24524242
DOI 10.1021/jm500059t
Crossref 10.1021/jm500059t
Uppsala Drug Optimization and Pharmaceutical Profiling (UDOPP) ADME of Therapeutics (UDOPP)