title: Orally bioavailable prodrugs of a BCS class 2 molecule, an inhibitor of HIV-1 reverse transcriptase.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304-1397, USA. todd.elworthy@Roche.com
authors.forename: Todd R
authors.initials: TR
authors.lastname: Elworthy
authors.forename: James P
authors.initials: JP
authors.lastname: Dunn
authors.forename: J Heather
authors.initials: JH
authors.lastname: Hogg
authors.forename: Grace
authors.initials: G
authors.lastname: Lam
authors.forename: Y David
authors.initials: YD
authors.lastname: Saito
authors.forename: Tania M P C
authors.initials: TM
authors.lastname: Silva
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Stefanidis
authors.forename: Witold
authors.initials: W
authors.lastname: Woroniecki
authors.forename: Eugenia
authors.initials: E
authors.lastname: Zhornisky
authors.forename: Amy S
authors.initials: AS
authors.lastname: Zhou
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002254:Carbonates / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D011355:Prodrugs / Q000737:chemistry; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D012995:Solubility
chemical_list: D002254:Carbonates; D004952:Esters; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase