Bis[(para-methoxy)benzyl] phosphonate prodrugs with improved stability and enhanced cell penetration.
A series of substituted bis[(para-methoxy)benzyl] (bisPMB) esters of 1-naphthalenemethylphosphonate (NMPA) were synthesized and evaluated as phosphonate prodrugs. BisPMB NMPA esters (4b and 4c) with significantly improved aqueous stability were identified that also resulted in increased intracellular levels of NMPA following prodrug incubation with primary rat hepatocytes.
Dang
Qun
Q
Department of Chemistry, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, CA 92037, USA. dang@mbasis.com
Liu
Yan
Y
Rydzewski
Robert M
RM
Brown
Brian S
BS
Robinson
Edward
E
van Poelje
Paul D
PD
Colby
Timothy J
TJ
Erion
Mark D
MD
D000818:Animals; D004355:Drug Stability; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008956:Models, Chemical; D063065:Organophosphonates / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D013997:Time Factors
D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C522192:bis((para-methoxy)benzyl) phosphonate