Prodrug discovery, oral

Cho A (2006) Recent advances in oral prodrug discovery. Ann Rep Med Chem 41 395-407... 

Penam Sulfone p-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of /i-lactainase inhibitors based on the readily accessible penicillin nucleus. An early success was peni-cillanic acid sulfone, (2(5)-ru)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-azabicyclo [3.2.0]heptane-2-carboxylic acid (sulbactam) (R = R1 = H,R2 = R = CH3), CsHnNOjS. The synthesis, microbiology, and clinical use of sulbactam have been reviewed. Sulbactam, with minor exceptions, is a weak antibacterial, but is a potent irreversible inactivator of many /3 lactamases, including penases and Richmond Sykes type 11, III, IV. V, and VI (Bactcroides) /3-lactamases. Sulbactam is better than clavulanic acid against type I Cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sul-fones have been reported to be /3-lactamase inhibitors. 

Beaumont, K., et al. 2003. Design of ester prodrugs to enhance oral absorption of poorly permeable compounds Challenges to the discovery scientist. Curr Drug Metab 4 461. 

Drug Discovery Today 7 25-27 Li AP (2004) In vitro approaches to evaluate ADMET drug properties. Curr Top Med Chem 4 701-706 Li W, Escarpe PA, Eisenberg EJ et al. (1998) Identification of GS 4104 as an orally bioavailable prodrug of the influenza virus neuraminidase inhibitor GS 4071. Antimicrobial Agents and Chemotherapy 42 647-653 Los LE, Welsh DA, Herold EG et al. (1996) Gender differences in toxicokinetics, liver metabolism, and plasma esterase activity observations from a chronic (27-week) toxicity study of enalapril/diltiazem combinations in rats. Drug Metab Dispos 24 28-33... 

Dang Q, Kasibhatla SR, Jiang T, Fan K, Liu Y, Taplin F, Schulz W, Cushion DK, Reddy KR, Poelje VPD, Fujitaki JM, Potter SC, Erion MD (2008) Discovery of phosphonic diamide prodrugs and their use for the oral delivery of a series of fructose 1,6-bisphosphatase inhibitors. J Med Chem 51 4331 339. doi 10.1021/jm8001235... 

Discovery of new HIV protease inhibitors and prodrug strategies for enhancing their oral bioavailability... 

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