7-alkylcarbonyl and 7-alkyloxycarbonyl prodrugs of theophylline.
Five members (6-10) of an homologous series of 7-alkyloxycarbonyltheophylline (7-AOC-Th) and four members (2-5) of a homologous series of 7-alkylcarbonyltheophylline (7-AC-Th) prodrugs have been synthesized by known methods and characterized. All of the members in both series were much more soluble in isopropyl myristate (S(IMP)) (10-200 times) and in each series, at least one member was more soluble in pH 4.0 buffer (S(AQ)) than Th. However, in the 7-AC-Th series, only the acetyl member, 2, which exhibited about 90% of the S(AQ) of Th, was sufficiently stable to be evaluated - it gave four times the flux of Th/IPM (isopropyl myristate). In the 7-AOC-Th series, all the members were sufficiently stable to be evaluated but the member which exhibited the greatest S(AQ), 6 (methyloxycarbonyl), did not exhibit the greatest flux. Instead, 8 (propyloxycarbonyl), which exhibited the second greatest S(AQ) (about 80% of the S(AQ) of Th), but exhibited over ten times the S(IPM) of 6 gave the greatest flux - two times the flux of Th/IPM. Thus, good biphasic solubility was the best predictor of increased flux. All of the prodrugs delivered only Th through the mouse skin. Only 2/IPM actually delivered more Th into the skin than Th/IPM which correlated with its ability to increase the flux of Th through the skin.
Sloan
K B
KB
Department of Medicinal Chemistry, University of Florida, PO Box 100485, Gainesville, FL 32610, USA. sloan@cop.ufl.edu
DellaVecchia
S A
SA
Estes
J V
JV
Roberts
W J
WJ
D000818:Animals; D006863:Hydrogen-Ion Concentration; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry*; D012869:Skin Absorption / Q000187:drug effects; D012995:Solubility; D013806:Theophylline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry*
D010726:Phosphodiesterase Inhibitors; D011355:Prodrugs; D013806:Theophylline