title: Acetylcholinesterase inhibitors: SAR and kinetic studies on omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl derivatives.
abstract: 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 omega-[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 IC(50) 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 IC(50) 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rampa
authors.forename: L
authors.initials: L
authors.lastname: Piazzi
authors.forename: F
authors.initials: F
authors.lastname: Belluti
authors.forename: S
authors.initials: S
authors.lastname: Gobbi
authors.forename: A
authors.initials: A
authors.lastname: Bisi
authors.forename: M
authors.initials: M
authors.lastname: Bartolini
authors.forename: V
authors.initials: V
authors.lastname: Andrisano
authors.forename: V
authors.initials: V
authors.lastname: Cavrini
authors.forename: A
authors.initials: A
authors.lastname: Cavalli
authors.forename: M
authors.initials: M
authors.lastname: Recanatini
authors.forename: P
authors.initials: P
authors.lastname: Valenti
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000737:chemistry; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase