Aminopyridine carbamic acid esters: Synthesis and potential as acetylcholinesterase inhibitors and acetylcholine releasers

Article abstract of DOI:10.1002/jps.2600810419

4-Amino-3-pyridyl carbamates (2a-c) were synthesized as potential acetylcholinesterase inhibitors and acetylcholine releasers on the basis of the reported activity of the analogous N-(4-amino-3-pyridyl)-N',N'- dimethylurea (1). Although 4-amino-3-pyridyl N,N-dimethylcarbamate (2b) showed good cholinesterase inhibition [concentration that elicited a 50% reduction in the maximal enzyme response (IC₅₀) was 13.4 μM], it had no effect on the stimulated release of [³H]acetylcholine from rat striatal slices. 4-[[(Dimethylamino)methylene]amino]-3-pyridyl N,N-dimethylcarbamate (7a), an intermediate in the synthesis of 2b, demonstrated surprisingly good cholinesterase inhibition (IC₅₀ was 9.4 μM) but showed no activity as a releaser. A precursor to 7a, N-(3-hydroxy-4-pyridyl)-N',N'- dimethylformamidine (6a), showed some activity in release but was not an esterase inhibitor, whereas the precursor to 6a, 4-amino-3-pyridinol (5a), was a potent releaser. A new synthesis of 5a, based on an ortho-directed lithiation strategy, is also reported.