Discovery of Phosphonic Diamide Prodrugs and Their Use for the Oral Delivery of a Series of Fructose 1,6-Bisphosphatase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 51; no. 14; pp. 4331 - 4339
• Main Authors: Dang, Qun, Kasibhatla, Srinivas Rao, Jiang, Tao, Fan, Kevin, Liu, Yan, Taplin, Frank, Schulz, William, Cashion, Daniel K, Reddy, K. Raja, van Poelje, Paul D, Fujitaki, James M, Potter, Scott C, Erion, Mark D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.07.2008; Amer Chemical Soc
• Subjects: Administration, Oral; Amides - chemistry; Animals; Biological and medical sciences; Blood Glucose - analysis; Chemistry, Medicinal; Drug Stability; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Fructose-Bisphosphatase - antagonists & inhibitors; General and cellular metabolism. Vitamins; Hydrogen-Ion Concentration; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Organophosphonates - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prodrugs - administration & dosage; Prodrugs - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; HIV-1; DESIGN; POTENT; FRUCTOSE-1,6-BISPHOSPHATASE; LEADS; PHOSPHATE DERIVATIVES; BIOAVAILABILITY; Fructose-bisphosphatase; Intravenous administration; Rat; Enzyme; Thiazole derivatives; Rodentia; Furan derivatives; Oral administration; Phosphoric monoester hydrolases; Propionic acid derivatives; Enzyme inhibitor; Esterases; Prodrug; In vitro; Phosphorus Organic compounds; In vivo; Vertebrata; Hypoglycemic agent; Mammalia; Structure activity relation; Animal; Hydrolases; Phosphonic acid derivatives; Chemical synthesis
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm8001235

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.