title: New huprine derivatives functionalized at position 9 as highly potent acetylcholinesterase inhibitors.
abstract: A series of 24 huprine derivatives diversely functionalized at position 9 have been synthesized and evaluated for their inhibitory activity against human recombinant acetylcholinesterase (AChE). These derivatives were prepared in one to five steps from huprine 1 bearing an ester function at position 9. Ten analogues (1, 2, 6-9, 13-15, and 23) are active in the low nanomolar range (IC(50) <5 nM), very close to the parent compound huprine X. Compounds 2, 6, and 7 show a very good selectivity for AChE, with AChE inhibitory activities 700-1160-fold higher than those for butyrylcholinesterase (BChE). The inhibitory potency of these compounds decreases with the steric bulk of the substituents at position 9. According to docking simulations, small substituents fit into the acyl-binding pocket, whereas the larger ones stick out of the active site gorge of AChE. Determination of the kinetic parameters of three of the most potent huprines (2, 6, and 7) showed that most of the difference in K(D) is accounted by a decrease in k(on) , which is correlated to the increase of the substituent size. A first in vivo evaluation has been performed in mice for the most active compound 2 (IC(50) =1.1 nM) and showed a rather weak toxicity (LD(50) =40 mg kg(-1) ) and an ability to cross the blood-brain barrier with doses above 15 mg kg(-1).
authors.affiliation: Equipe de Chimie Bio-organique, COBRA-CNRS UMR 6014 & FR 3038, Mont-Saint-Aignan, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Ronco
authors.forename: Richard
authors.initials: R
authors.lastname: Foucault
authors.forename: Emilie
authors.initials: E
authors.lastname: Gillon
authors.forename: Pierre
authors.initials: P
authors.lastname: Bohn
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
authors.forename: Ludovic
authors.initials: L
authors.lastname: Jean
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Renard
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D011994:Recombinant Proteins; C404518:huprine X; D000110:Acetylcholinesterase