Small-molecule inhibitor: indinavir

Name

History: Key early publications were those of Dorsey et al. (1994) and Vacca et al. (1994), and the history if the development of indinavir has been reviewed by Wlodawer & Vondrasek (1998).
Peptidases inhibited: Indinavir is a highly selective inhibitor of the retropepsins of the HIV-1 and HIV-2 viruses (A02.001 and A02.002, respectively) (Dorsey et al., 1994). Inhibition of the retropepsin of human endogenous retrovirus) is weak (Towler et al., 1998) and that of porcine endogenous retrovirus retropepsin) is negligible (Qari et al., 2001).
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Indinavir was approved for drug use against HIV infection under the name Crixivan in 1996 (Merck).
DrugBank: DB00224

CID at PubChem: 60944
ChEBI: 44032
Structure
Chemical/biochemical name: (2S)-1-[(2S,4R)-2-hydroxy-4-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamoyl]-5-phenyl-pentyl]-4-(pyridin-3-ylmethyl)-N-tert-butyl-piperazine-2-carboxamide
Formula weight: 614
Related inhibitors: Compounds L-682,679, L-685,434, AG-1002 and AG-1004 were intermediates in the design of indinavir and nelfinavir (Wlodawer & Vondrasek, 1998).

Inhibitor class: This compound is of the peptide isostere class of aspartic peptidase inhibitors. The discovery of pepstatin drew attention to the fact that structural analogues of the scissile bond that are not hydrolysable but mimic the transition state in catalysis can be potent reversible inhibitors of peptidases. Development of such inhibitors for aspartic peptidases was driven by the need for drugs against AIDS (Roberts et al., 1990). Structural analogues of the peptide bond that have been used include hydroxyethylene, difluorostatone, statine, phosphinate and reduced amide. It was found that pepstatin inhibits retropepsin (Seelmeier et al., 1988; Richards et al., 1989), but there was a need for potent inhbitors of retropepsin that would not interact with mammalian aspartic peptidases such as pepsin. A key development was the discovery that retropepsins have the unusual ability to cleave bonds with S1" proline, and it was discovered that proline could be replaced by analogues such as pipecolic acid in inhibitors (Copeland et al., 1990).The development of such inhibitors as drugs, and the contribution that structure-based drug design has made to it, have been lucidly reviewed by Wlodawer and colleagues (Wlodawer & Erickson, 1993; Wlodawer & Vondrasek, 1998).