Orally bioavailable prodrugs of a BCS class 2 molecule, an inhibitor of HIV-1 reverse transcriptase.
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.
Elworthy
Todd R
TR
Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304-1397, USA. todd.elworthy@Roche.com
Dunn
James P
JP
Hogg
J Heather
JH
Lam
Grace
G
Saito
Y David
YD
Silva
Tania M P C
TM
Stefanidis
Dimitrios
D
Woroniecki
Witold
W
Zhornisky
Eugenia
E
Zhou
Amy S
AS
Klumpp
Klaus
K
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
D002254:Carbonates; D004952:Esters; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase