Combinatorial diversification of indinavir: in vivo mixture dosing of an HIV protease inhibitor library

T A Rano; Y Cheng; T T Huening; F Zhang; W A Schleif; L Gabryelski; D B Olsen; L C Kuo; J H Lin; X Xu; T V Olah; D A McLoughlin; R King; K T Chapman; J R Tata

doi:10.1016/s0960-894x(00)00276-6

Combinatorial diversification of indinavir: in vivo mixture dosing of an HIV protease inhibitor library

Bioorg Med Chem Lett. 2000 Jul 17;10(14):1527-30. doi: 10.1016/s0960-894x(00)00276-6.

Authors

T A Rano¹, Y Cheng, T T Huening, F Zhang, W A Schleif, L Gabryelski, D B Olsen, L C Kuo, J H Lin, X Xu, T V Olah, D A McLoughlin, R King, K T Chapman, J R Tata

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]

PMID: 10915042
DOI: 10.1016/s0960-894x(00)00276-6

Abstract

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.

MeSH terms

Animals
Cell Line
Combinatorial Chemistry Techniques*
Dogs
HIV Protease / metabolism
HIV Protease Inhibitors / chemical synthesis
HIV Protease Inhibitors / chemistry*
HIV Protease Inhibitors / pharmacokinetics
HIV Protease Inhibitors / pharmacology
Humans
Indinavir / analogs & derivatives*
Indinavir / chemical synthesis
Indinavir / chemistry*
Indinavir / pharmacokinetics
Indinavir / pharmacology
Models, Molecular
Molecular Conformation
Molecular Structure
T-Lymphocytes

Substances

HIV Protease Inhibitors
Indinavir
HIV Protease