The Design, Synthesis and Screening of Potential Pyridinium Oxime Prodrugs
Abstract
In an attempt to improve the delivery of quaternary pyridinium oxime regenerators of acetylcholinesterase (AChE) to the Central Nervous System (CNS), structural analogs and prodrugs of N-methylpyridinium 2-carbaldoxime (2-PAM) have been synthesized. The Series I prodrugs are dihydropyridinium oximes (pro- 2-PAM's) which possess electron withdrawing substituents in the 3- or 5- position. As precursors to these Series I prodrugs several 5-substituted-2-PAM's (I, Br substituted) and a 3-substituted 2-PAM (I-substituted) have been synthesized and characterized. In vitro and in vivo (mice) screening of these compounds indicates some promise as AChE regenerators, prompting the preparation of gram quantities of the I-substituted oximes for further biological evaluation. Efforts toward the synthesis of other 3- or 5-substituted (CN, COHN2 substituted) oximes were initiated. The Series II prodrugs are tetrahydropyridinium oximes were initiated. The Series II prodrugs are tetrahydropyridinium oximes which possess a labile ring substituent. These mashed prodrugs (double latentiation) are addition products of pro-2-PAM.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 1984
- Accession Number
- ADA184480
Entities
People
- John E. Simmons
- Ronald T. Borchardt
Organizations
- University of Kansas