The Design, Synthesis and Screening of Potential Pyridinium Oxime Prodrugs.
Abstract
In an attempt to improve the CNS delivery of quaternary pyridinium oxime regenerators of acetylcholinesterase (AChE), we have initiated chemical and biochemical studies on structural analogs and prodrug forms of N-methylpyridinium 2-carbaldoxime (2-PAM, 7). Over the past year we have concentrated our efforts on synthesizing two basic types of Pro-PAM derivatives. Series I are dihydropyridinium oximes 1 and 2 which possess electron withdrawing substituents in the 3- or 5-position. These compounds require oxidation (latentation) to generate the substituted 2-PAMs 5 and 6. It is hoped that the electron withdrawing substituent will stabilize the dihydropyridine structure and produce a slow in vitro conversion. Series II are tetra-hydropyridinium oximes 3 which possess a labile ring substituent. These masked prodrugs (double latentation) are addition products of dihydropyridinium oxime 4 (Pro-2-PAM) and require a two step (elimination and oxidation) conversion to the active quaternary oxime 7 (2-PAM).
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 1983
- Accession Number
- ADA189325
Entities
People
- John E. Simmons
- Ronald T. Borchardt
Organizations
- University of Kansas