- Combinatorial diversification of indinavir: In vivo mixture dosing of an HIV protease inhibitor library
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An efficient combination solution-phase/solid-phase route enabling the diversification of the P1', P2', and P3 subsites of indinavir has been established. The synthetic sequence can facilitate the rapid generation of HIV protease inhibitors possessing more favorable pharmacokinetic properties as well as enhanced potencies. Multiple compound dosing in vivo may also accelerate the identification of potential drug candidates. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Rano, Thomas A.,Cheng, Yuan,Huening, Tracy T.,Zhang, Fengqi,Schleif, William A.,Gabryelski, Lori,Olsen, David B.,Kuo, Lawrence C.,Lin, Jiunn H.,Xu, Xin,Olah, Timothy V.,McLoughlin, Debra A.,King, Richard,Chapman, Kevin T.,Tata, James R.
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p. 1527 - 1530
(2007/10/03)
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- L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor
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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.
- Dorsey,Levin,McDaniel,Vacca,Guare,Darke,Zugay,Emini,Schleif,Quintero,Lin,Chen -,Holloway,Fitzgerald,Axel,Ostovic,Anderson,Huff
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p. 3443 - 3451
(2007/10/02)
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