Protease inhibitors based

The introduction of protease inhibitor-based regimens seemed to be responsible for a change within the structure of provider costs. There is some evidence that the share of drugs increased, whereas the importance of hospitalization declined. For instance, Hellinger (1993) estimated that drug costs to account for about 10% of the total provider costs, whereas the inpatient hospitals costs were responsible for some... 

Y Hamada, J Ohtake, Y Sohma, T Kimura, Y Hayashi, Y Kiso. New water-soluble prodrugs of HIV protease inhibitors based on 0—>N intramolecular acyl migration. Bioorg Med Chem 10, 4155, 2002. 

Milne et al. described the discovery of HIV-1 protease inhibitors based on a pharmacophore derived from X-ray crystal structures. After searching the NCI database with 206 000 entries and postfiltering the resulting hits, a total of 50 molecules were tested, leading to submicromolar activity for the best two compounds [286]. In their search for HIV-1 integrase inhibitors, another pharmacophore produced up to 340 hits, resulting in 10 structurally different classes and four compounds with affinities below 30 XM [287]. 

Calza L, Manfredi R, Farneti B, Chiodo F. Incidence of hyperlipidaemia in a cohort of 212 HIV-infected patients receiving a protease inhibitor-based antiretroviral therapy. Int J Antimicrob Agents 2003 22 54-9. 

Examples of peptide-peptoid hybrid serine protease inhibitors based on the trypsin inhibitor SFTI-1 with complete protease resistance at the Pl-Pl reactive site. Chembiochem. 6, 1057-1061. 

Protease Inhibitors Based on Multifunctional Mucoadhesive Polymers. . 75... 

Moreno A, Perez-Elias MJ, Casado JL, Munoz V, Antela A, Dronda F, Navas E, Moreno S. Long-term outcomes of protease inhibitor-based therapy in antiretroviral treatment-naive HIV-infected injection drug users on methadone maintenance programmes. AIDS 2001 15(8) 1068-70. 

Becker SL. The role of pharmacological enhancement in protease inhibitor-based highly active antirehovhal therapy. Exp Opin Invest Drugs 2003 12 401-412. 

To evaluate the biological applicability of this design, Smith and Hirschmann have developed HIV-1 protease inhibitors based on the polypyrrolinone scaffold. Previous studies have shown that many binding interactions are conserved in the HIV-1 protease/inhibitor complex formation [36]. /3-Strand peptide inhibitors, such as 5 and JG-365 (Ac-Ser-Leu-Asn-Phe-Hea-Pro-Ile-Val-OMe, Hea - hydroxylamine [CH(OH)CH2N]), bind in an active site on the HIV-1 protease surface with their side chains inserting into hydrophobic pockets (Fig. 4.3-4). 

A. Pasternak, W.Q. Yao, P.A. Sprengeler, M.K. Holloway, L.C. Kuo, Z.G. Chen, P.L. Darke, W.A. Schleif, An orally bioavailable pyrrolinone inhibitor of Hiv-1 protease computational analysis and X-ray crystal structure of the enzyme complex, J. Med. Chem. 1997, 40, 2440-2444 P.V. Murphy, J.L. O Brien, L.J. Gorey-Feret, A.B. Smith, Synthesis of novel Hiv-1 protease inhibitors based on carbohydrate scaffolds, Tetrahedron 2003, 59, 2259-2271 P.V. Murphy, J.L. O Brien, L.J. Gorey-Feret, A.B. Smith, Structure-based design and synthesis of Hiv-1 protease inhibitors employing beta-D-mannopyranoside scaffolds, Bioorg. Med. Chem. Lett. 2002, 12, 1763-1766. 

Use of protease inhibitor-based regimens has been found to be associated with a higher incidence of infections and neutropenia in patients receiving cyciophosphamide, doxorubicin and etoposide (CDE) than use of a NNRTI-based regimen. 

Rezacova, P., Pokoma, J., Brynda, J. et al. 2009. Design of HIV protease inhibitors based on inorganic polyhedral metallacarboranes. 7. Med. Chem. 52 7132-7141. 

A more detailed discussion on HIV protease inhibitors based on cobalt bis(dicarbollide) is available in Chapter 4. 

---