Aminopyridine carbamic acid esters: synthesis and potential as acetylcholinesterase inhibitors and acetylcholine releasers.
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 microM], 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 microM) but showed no activity as a release. 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.
Shutske
G M
GM
Department of Chemical Research, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ 08876.
Tomer
J D
JD
Kapples
K J
KJ
Hrib
N J
NJ
Jurcak
J G
JG
Bores
G M
GM
Huger
F P
FP
Petko
W
W
Smith
C P
CP
D000109:Acetylcholine / Q000378:metabolism*; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000631:Aminopyridines; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D000109:Acetylcholine