Table 1.
Examples of successful strategies applied for the discovery of protease inhibitors
| Disease | Protease (class) |
Drug name (trade name; company) |
Drug type |
Drug structure | Hits by | Date on market |
Refs |
|---|---|---|---|---|---|---|---|
| Hypertension | ACE (metallo) |
Captopril (Capoten; Brystol-Myers Squibb) |
Peptidic |
|
De novo (structure- based drug screening |
1981 | 2 |
| Hypertension | Renin (aspartic) |
Aliskiren (Tekturna/Rasilez; Novartis/Speedel) |
Non- peptidic |
|
De novo (structure- based drug screening) |
2007 | 108 |
| HIV/AIDS | HIV protease (aspartic) |
Tipranavir (Aptivus; Pfizer/ Boehringer Ingelheim) |
Non- peptidic |
|
Derived from a non-peptidic screening programme |
2005 | 3 |
| Cancer | Proteasome (threonine) |
Bortezomib (Velcade; Millennium) |
Peptidic |
|
De novo (systematic optimization studies) |
2003 | 27 |
| Diabetes | DPP4 (serine) |
Sitagliptin (Januvia; Merck) |
Non- peptidic |
|
Optimization of a class of β-amino acids |
2006 | 35 |
| Coagulation | Thrombin (serine) |
Desirudin (Revasc/Iprivask; Novartis) |
Peptidic | Polypeptide (65 amino acid residues) | Isolated from the medicinal leech Hirudo medicinalis |
1998 | 129 |
| Coagulation | Factor Xa (serine) |
Rivaroxaban (Xarelto; Bayer) |
Non- peptidic |
|
Product from HTS and subsequent de novo systematic optimization studies |
2008 | 130 |
| Coagulation | Thrombin (serine) |
Dabigatran (Rendix/Pradaxa; Boehringer Ingelheim) |
Non- peptidic |
|
De novo (systematic optimization studies) |
2008 | 131 |
| Coagulation | Thrombin (serine) |
Argatroban (Acova; GlaxoSmithKline) |
Non- peptidic |
|
De novo (systematic optimization studies) |
2000 | 132 |
ACE, angiotensin-converting enzyme; DPP, dipeptidyl peptidase; HTS, high-throughput screening.