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Acetylcholinesterase Inhibitors: SAR and Kinetic Studies on ω-[ N -Methyl- N -(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl Derivatives

2001; American Chemical Society; Volume: 44; Issue: 23 Linguagem: Inglês

10.1021/jm010914b

1520-4804

Angela Rampa, Lorna Piazzi, Federica Belluti, Silvia Gobbi, Alessandra Bisi, Manuela Bartolini, Vincenza Andrisano, Vanni Cavrini, Andrea Cavalli, Maurizio Recanatini, Piero Valenti,

Enzyme function and inhibition

In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new ω-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure−activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC50 value for the AChE inhibition of 0.32 ± 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC50 value of 3.3 ± 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.