| Organophosphorus-containing pesticides and chemical warfare agents are potent inhibitors of synaptic acetylcholinesterase, a key regulator of cholinergic neurotransmission. These nerve agents have for many years constituted a serious threat to military forces. These threats stimulated considerable efforts to develop effective medical countermeasures. Several potential drugs have been found recently which are capable of protecting animals and possibly humans from lethal or prolonged incapacitating effects of these agents. Drug development in general and drug design in particular, has depended in the past on the medicinal chemist to design, synthesize, and test potential drugs with total reliance on the trial and error method. Leading antidotes developed via the classical drug development technique include 2-PAM Chloride, Toxogonin, TMB-4, and HI-6. Recent USAMRDC drug development projects resulted in the synthesis of several hundred imidazolium oximes having activity against the most potent nerve gas, soman. This research was carried out to determine if these potential nerve agent antidotes could have been discovered through the use of Quantitative Structure-Activity Relationship (QSAR) technique. The Hansch approach to QSAR, with all its multiple parameter regression equations, was utilized for this purpose. |
