Discovery of phosphonic diamide prodrugs and their use for the oral delivery of a series of fructose 1,6-bisphosphatase inhibitors.
Like most phosphonic acids, the recently discovered potent and selective thiazole phosphonic acid inhibitors of fructose 1,6-bisphosphatase (FBPase) exhibited low oral bioavailability (OBAV) and therefore required a prodrug to achieve oral efficacy. Syntheses of known phosphonate prodrugs did not afford the desired OBAV; hence, a new class of prodrugs was sought. Phosphonic diamides derived from amino acid esters were discovered as viable prodrugs, which met our preset goals: excellent aqueous stability over a wide pH range, benign byproducts (amino acids and low molecular weight alcohols), and most importantly good OBAV leading to robust oral glucose lowering effects. These desirable properties of phosphonic diamides represent significant improvements over existing prodrug classes. Optimization of the diamide prodrugs of phosphonic acid 2a (MB05032) led to the identification of diamide 8 (MB06322), the first reported orally efficacious FBPase inhibitor.
Department of Medicinal Chemistry, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, California 92037, USA. dang@mbasis.com
Qun
Q
Dang
Srinivas Rao
SR
Kasibhatla
Tao
T
Jiang
Kevin
K
Fan
Yan
Y
Liu
Frank
F
Taplin
William
W
Schulz
Daniel K
DK
Cashion
K Raja
KR
Reddy
Paul D
PD
van Poelje
James M
JM
Fujitaki
Scott C
SC
Potter
Mark D
MD
Erion
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006597:Fructose-Bisphosphatase / Q000037:antagonists & inhibitors*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D063065:Organophosphonates / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000577:Amides; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011355:Prodrugs; D006597:Fructose-Bisphosphatase