Small-molecule inhibitor: amprenavir

Name

Common name: amprenavir
Other names: Agenerase; Fosamprenavir (prodrug); GW433908 (prodrug); 141W94; VX478

Peptidases inhibited: Inhibitor of the retropepsins of the HIV-1 and HIV-2 viruses (A02.001 and A02.002, respectively: Tisdale et al., 1995). Mutations in the sequence of retropepsin can increase or decrease its sensitivity to inhibition by amprenavir (Gallego et al., 2002; Murphy et al., 2004). There is no significant inhibition of porcine endogenous retrovirus retropepsin: Qari et al., 2001). Inhibits cytochrome P450 3A (CYP3A), slowing the metabolism of other retropepsin inhibitors (von Moltke et al., 2000).
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Amprenavir (Vertex) is approved as a drug for the treatment of AIDS (Billich, 1999).
DrugBank: DB00701

CID at PubChem: 65016
ChEBI: 40050
Structure
Chemical/biochemical name: oxolan-3-yl [4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenyl-butan-2-yl]aminoformate
Formula weight: 506
Related inhibitors: GW433908, a phosphate ester prodrug of amprenavir. Fosamprenavir is a prodrug (Wire et al., 2006).

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).
Reviews: Fung et al. (2000); Noble & Goa (2000)