174139-99-2Relevant articles and documents
L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor
Dorsey,Levin,McDaniel,Vacca,Guare,Darke,Zugay,Emini,Schleif,Quintero,Lin,Chen -,Holloway,Fitzgerald,Axel,Ostovic,Anderson,Huff
, p. 3443 - 3451 (2007/10/02)
A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with K(i) values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1(IIIb)-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.
