ANTIRHINO ENTEROVIRAL VINYLACETYLENE BENZIMIDAZOLES - A STUDY OF THEIR ACTIVITY AND ORAL PLASMA-LEVELS IN MICE/

In an effort to find an orally bioavailable antiviral for the treatmen t of rhino/enteroviral infections, a series of vinylacetylene benzimid azoles (11a-o, 12, and 18a was made. Initial studies of this class of antivirals showed that fluorine substitution on the left-hand phenyl r ing in combination with the vinylacetylene moiety gave the requisite m ix of physical properties to achieve good in vitro antiviral activity as well as respectable oral bioavailability in rhesus monkeys. To asce rtain the generality of this finding and to broaden the scope of the s tructure-activity relationship (SAR), the present study concentrated o n fluoro substitution of this class of molecules. The initial antivira l activity for each analogue was measured using human rhinovirus 14 (H RV-14). This served as an indicator of general antiviral activity for SAR purposes. Subsequently, the spectrum of antirhino/enteroviral acti vity of the more interesting analogues was evaluated through testing a gainst a panel of seven additional rhino/enteroviruses. Broad-spectrum activity was present and consistent for all analogues tested, and it tracked closely with the antiviral activity observed against HRV-14. A simple screening protocol for oral bioavailability was established wh ereby compounds were administered orally to mice and plasma levels wer e measured. This procedure facilitated the evaluation of numerous anal ogues in a rapid manner. The C-max was used as a measure of oral bioav ailability to allow relative ranking of compounds. In general, fluorin e substitution directly on the left-hand aromatic ring does give good oral blood levels. However, fluorine incorporation at other positions in the molecule was not as effective at maintaining either the activit y or the oral plasma levels. The constructive combination of activity and oral plasma levels was maximized in three derivatives: 11a,e,g.