Small-molecule inhibitor: darunavir

Name

History: The compound was described by Koh et al. (2003), and the history of development from TMC-126 was described by Shurtleff (2004).
Peptidases inhibited: Inhibits the retropepsins of the HIV-1 and HIV-2 viruses (A02.001 and A02.002, respectively).
Mechanism: Inhibition is reversible. Reported to be a much more potent inhibitor than amprenavir (King et al., 2004). Structures of complexes with HIV-1 retropepsin have been described by King et al. (2004).
Pharmaceutical relevance: A mixture of duranavir with ritonavir demonstrated a potent antiretroviral effect over 14 days in multiple-PI-experienced patients (Arasteh et al., 2005).
DrugBank: DB01264

CID at PubChem: 3001874
ChEBI: 456598
Structure
Chemical/biochemical name: 4,6-dioxabicyclo[3.3.0]oct-8-yl [4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenyl-butan-2-yl]aminoformate
Formula weight: 548

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).
Comment: A sulphonamide compound.