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Design, synthesis, and biological evaluation of conformationally restricted rivastigmine analogues.
J Med Chem. 2004 Nov 18; 47(24):5945-52.JM

Abstract

Rivastigmine (1), an acetylcholinesterase (AChE) inhibitor approved in 2000 for the treatment of Alzheimer disease, bears a carbamate moiety in its structure, which is able to react covalently with the active site of the enzyme. Kinetic and structural studies on the interaction of 1 with different cholinesterases have been published, giving deeper, but not definitive, insights on the catalysis mechanism. On the basis of these findings and in connection with our previous studies on a series of benzopyrano[4,3-b]pyrrole carbamates as AChE inhibitors, we designed a series of conformationally restricted analogues of 1 by including the dimethylamino-alpha-methylbenzyl moiety in different tricyclic systems. A superimposition between the conformation of 1 and the carbon derivative 4, as obtained from Monte Carlo simulations, supported the idea that the tricyclic derivatives might act as rigid analogues of 1. The biological profile of 4-9, assessed in vitro against human AChE and BChE, validated our rational design. Compound 5, bearing a sulfur-containing system, showed the highest inhibitory activity, being 192-fold more potent than 1. In the present study, the most potent inhibitors were always methyl derivatives 3-5, endowed with a nanomolar range potency, whereas the ethyl ones were 40 times less potent. A reasonable explanation for this finding might be a steric hindrance effect between the ethyl group of 1 and His440 in the active site, as already suggested by the crystal structure of the complex AChE/1. The unfavorable influence of the carbamic N-alkyl chain on AChE inhibition is less striking when considering BChE inhibition, since BChE is characterized by a bigger acyl binding pocket than AChE. In fact, methyl carbamates 3-5 did not show AChE/BChE selectivity, whereas compounds 6-9 were significantly more potent in inhibiting BChE than AChE activity. At 100 microM, 5 was found to inhibit the AChE-induced aggregation only by 19% likely because it is not able to strongly interact with the peripheral anionic site of AChE, which plays an essential role in the Abeta aggregation mediated by the enzyme but is lacking in BChE structure.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15537349

Citation

Bolognesi, Maria Laura, et al. "Design, Synthesis, and Biological Evaluation of Conformationally Restricted Rivastigmine Analogues." Journal of Medicinal Chemistry, vol. 47, no. 24, 2004, pp. 5945-52.
Bolognesi ML, Bartolini M, Cavalli A, et al. Design, synthesis, and biological evaluation of conformationally restricted rivastigmine analogues. J Med Chem. 2004;47(24):5945-52.
Bolognesi, M. L., Bartolini, M., Cavalli, A., Andrisano, V., Rosini, M., Minarini, A., & Melchiorre, C. (2004). Design, synthesis, and biological evaluation of conformationally restricted rivastigmine analogues. Journal of Medicinal Chemistry, 47(24), 5945-52.
Bolognesi ML, et al. Design, Synthesis, and Biological Evaluation of Conformationally Restricted Rivastigmine Analogues. J Med Chem. 2004 Nov 18;47(24):5945-52. PubMed PMID: 15537349.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and biological evaluation of conformationally restricted rivastigmine analogues. AU - Bolognesi,Maria Laura, AU - Bartolini,Manuela, AU - Cavalli,Andrea, AU - Andrisano,Vincenza, AU - Rosini,Michela, AU - Minarini,Anna, AU - Melchiorre,Carlo, PY - 2004/11/13/pubmed PY - 2005/1/4/medline PY - 2004/11/13/entrez SP - 5945 EP - 52 JF - Journal of medicinal chemistry JO - J Med Chem VL - 47 IS - 24 N2 - Rivastigmine (1), an acetylcholinesterase (AChE) inhibitor approved in 2000 for the treatment of Alzheimer disease, bears a carbamate moiety in its structure, which is able to react covalently with the active site of the enzyme. Kinetic and structural studies on the interaction of 1 with different cholinesterases have been published, giving deeper, but not definitive, insights on the catalysis mechanism. On the basis of these findings and in connection with our previous studies on a series of benzopyrano[4,3-b]pyrrole carbamates as AChE inhibitors, we designed a series of conformationally restricted analogues of 1 by including the dimethylamino-alpha-methylbenzyl moiety in different tricyclic systems. A superimposition between the conformation of 1 and the carbon derivative 4, as obtained from Monte Carlo simulations, supported the idea that the tricyclic derivatives might act as rigid analogues of 1. The biological profile of 4-9, assessed in vitro against human AChE and BChE, validated our rational design. Compound 5, bearing a sulfur-containing system, showed the highest inhibitory activity, being 192-fold more potent than 1. In the present study, the most potent inhibitors were always methyl derivatives 3-5, endowed with a nanomolar range potency, whereas the ethyl ones were 40 times less potent. A reasonable explanation for this finding might be a steric hindrance effect between the ethyl group of 1 and His440 in the active site, as already suggested by the crystal structure of the complex AChE/1. The unfavorable influence of the carbamic N-alkyl chain on AChE inhibition is less striking when considering BChE inhibition, since BChE is characterized by a bigger acyl binding pocket than AChE. In fact, methyl carbamates 3-5 did not show AChE/BChE selectivity, whereas compounds 6-9 were significantly more potent in inhibiting BChE than AChE activity. At 100 microM, 5 was found to inhibit the AChE-induced aggregation only by 19% likely because it is not able to strongly interact with the peripheral anionic site of AChE, which plays an essential role in the Abeta aggregation mediated by the enzyme but is lacking in BChE structure. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/15537349/Design_synthesis_and_biological_evaluation_of_conformationally_restricted_rivastigmine_analogues_ L2 - https://doi.org/10.1021/jm049782n DB - PRIME DP - Unbound Medicine ER -