Aminopyridine Carbamic Acid Esters: Synthesis and Potential as Acetylcholinesterase Inhibitors and Acetylcholine Releasers

Abstract

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.