Discovery of Next Generation Inhibitors of HIV Protease

Andrew      Spaltenstein; Wieslaw   M.   Kazmierski; John   F.   Miller; Vicente      Samano

Abstract

Due to factors such as resistance and long-term side effects as well as dosing regimen-related adherence issues, HIV therapy is a constantly moving target. HIV-1 protease inhibitors had an immediate and dramatic impact on the outcome of HIV/AIDS when launched in late 1995, and the search for new and improved next generation molecules has been under way in many laboratories. At GlaxoSmithKline (GSK) and Vertex Pharmaceuticals, this effort focused on two key issues, patient compliance and viral resistance. Using a water-solubilizing prodrug approach, the pill-burden in delivering our protease inhibitor, amprenavir, was dramatically decreased. By eliminating the large amounts of excipients necessary for the original soft-gel formulation, fosamprenavir (Lexiva®/Telzir®) delivers the clinically efficacious dose of amprenavir with two compact tablets per dose, compared to eight gel capsules. Our efforts to overcome viral resistance to 1st generation protease inhibitors by further elaborating the SAR of the amprenavir and related scaffolds, led to successive and dramatic improvements in wild-type antiviral potencies, and ultimately to the discovery of "ultra-potent" molecules with very favorable overall resistance profiles. The selection of GW640385 (brecanvir - USAN approved only) as a clinical candidate and its progression into current phase 2 dose ranging studies represents the culmination of our effort toward next generation protease inhibitors.

Keywords: HIV, protease, inhibitors, ultrapotent, resistance, AIDS, brecanavir, prodrug, fosamprenavir