Page - (000070) - in Biomedical Chemistry: Current Trends and Developments

Figure 1.2.7: The crystal structure of inhibitor K777 bound to cruzain (pdb 2OZ2). The insert shows the interaction of K777 with the primary recognition site (S2) and secondary recognition sites (S1 and S3) of cruzain. 1.2.3.2 Rupintrivir (AG7088) The human rhinovirus 3C protease (3CP) belongs to clan PA(C). Because the rhinoviral protease (3CP) is specific to rhinovirus, inhibitors of this protease should have few side effects in humans. Several compounds containing a Michael acceptor moiety were described as potent Human rhinovirus (HRV) 3C protease inhibitors (Santos, 2007). Specifically, Rupintrivir (also known as Ruprintrivir or AG7088) was developed by Agouron Pharmaceuticals to treat HRV infections (Fig. 1.2.6). Rupintrivir is an α,β-unsaturated carbonyl that irreversibly inhibits the HRV 3C protease and shows potent, broad-spectrum anti-HRV activity in vitro (Hayden, 2003). The phase I and phase II results showed good safety and pharmacokinetic profiles. Although it successfully completed the initial Phase II trials (Hayden, 2003), due to lack of efficacy in natural infection studies, further development of Rupintrivir was stopped in PhaseII/III trials (http://www.drugdevelopment- technology.com/projects/ag7088/). 1.2.4 Case Study 2: From Covalent Inhibitors to Hybrid Drugs The design of hybrid compounds is a widely used strategy to improve