Orally bioavailable prodrugs of a BCS class 2 molecule, an inhibitor of HIV-1 reverse transcriptase

• Published in: Bioorganic & medicinal chemistry 2008-12, Vol.18 (24), p.6344-6347
• Main Authors: Elworthy, Todd R., Dunn, James P., Hogg, J. Heather, Lam, Grace, Saito, Y. David, Silva, Tania M.P.C., Stefanidis, Dimitrios, Woroniecki, Witold, Zhornisky, Eugenia, Zhou, Amy S., Klumpp, Klaus
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Biological Availability; Carbonates - chemistry; Chemistry, Pharmaceutical - methods; Class 2 molecule; Dissolution limiting pharmacokinetics; Drug Design; Esters - chemistry; HIV Reverse Transcriptase - chemistry; HIV-1 - enzymology; HIV-1 reverse transcriptase inhibitor; Human immunodeficiency virus 1; Hydrogen-Ion Concentration; Hydroxymethyl derivatives; Medical sciences; Models, Chemical; NNRTI; Oral bioavailability; Pharmacology. Drug treatments; Prodrug; Prodrugs - chemistry; Pyridazinone; Rats; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - pharmacokinetics; Solubility
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.10.090

Pyridazinone 1 was derivatized into a series of hydroxymethyl esters, carbonates and one phosphate. These prodrugs were orally dosed to rats and afforded increases of 4.3- to 8.6-fold in 24-hour exposure of 1 (over that of parent) and not detected in blood plasma. The N-2 position of pyridazinone 1, a potent HIV-1 NNRTI that has limited aqueous solubility, was derivatized into a series of hydroxymethyl esters and carbonates as well as one phosphate. The derivatives served as prodrugs to effectively deliver 1 to rat plasma upon oral treatment at 50 mpk. Increases of 4.3- to 8.6-fold in 24-hour exposure of 1 (over that of parent) were observed while the prodrugs and the hydroxymethyl adduct 2 were undetectable.