The Design and Synthesis of Orally Active Inhibitors of Botulinum Toxin Metalloproteases

Our goal was to design, synthesize and screen noval organic chemicals designed to inhibit all or several of the known botulinum toxin (BoNT)-metalloproteases. We have succeeded in demonstrating the feasibility of our approach to the design of botulinum inhibitors based on using the weak activity of captopril as a lead compound. We report the first prototype compounds that exceed our captopril lead compound by at least an order of magnitude in inhibitory properties. Such activity could be substrantially enhanced by the resolution of the stereo enteriomeric compounds into the optical isomer possessing the biological activity.