Journal Article
The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity
Kosak, U; Podkowa, A; Nachon, F; Brazzolotto, X; Stojan, J; Kos, J; Coquelle, N; Salat, K; Colletier, JP; Gobec, S; Brus, B; Knez, D; Zakelj, S; Trontelj, J; Pislar, A; Sink, R; Jukic, M; Zivin, M; ,
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804
AMER CHEMICAL SOC
The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-pi interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.
)tert butyl[2 [n [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] 2 naphthamido]ethyl](methyl)carbamate; )tert butyl[[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl][2 (dimethylamino)ethyl]carbamate; 1 benzoyl n [2 (dimethylamino)ethyl]piperidine 3 carboxamide; 1 benzoyl n [3 (dimethylamino)propyl]piperidine 3 carboxamide; 2 [(tert butoxycarbonyl)(methyl)amino]ethylmethanesulfonate; 6 bromo n [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] n (2 methoxyethyl0 2 naphthamide; cholinesterase inhibitor; n 1 [(1 benzylpiperidin 3 yl)methyl] n 2,n 2 dimethylethane 1,2 diamine; n 1 [(1 benzylpiperidin 3 yl)methyl] n 3.n 3 dimethylpropane 1,3 diamine; n 1 [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] n 2,n 2 dimethylethane 1,2 diamine tris(2,2,2 trifluoroacetate); n 1 [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] n 3,n 3 dimethylpropane 1,3 diamine tri(2,2,2 trifluoroacetate); n [(1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] n [3 (dimethylamino)propyl] 2 naphthamide; n [(1 benzylpiperidin 3 yl)methyl] 2 naphthamide; n [(1 benzylpiperidin 3 yl)methyl] n [2 (dimethylamino)ethyl] 2 naphthamide; n [(1 benzylpiperidin 3 yl)methyl] n [3 (dimethylamino)propyl] 2 naphthamide; n [(1 benzylpiperidin 3 yl)methyl]- n (2 methoxyethyl) 2 naphthamide; n [(1 benzylpiperidin 4 yl)methyl] 2 methoxyethan 1 amine; n [(1 benzylpiperidin 4 yl)methyl] n (2 methoxyethyl) 2 naphthamide; n [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] 1 naphthamide; n [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] n (3 methoxypropyl) 2 napththamide; n [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] n [2 (dimethylamino)ethylo] 2 naphthamide; n [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] n [2 (dimethylamino)ethyl] 2 naphthamide dichloride; n [[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl]methyl] n [2 (methylamino)ethyl] 2 naphthamide dihydroxhloride; n [[1 (benzo[d]thiazol 2 ylmethyl)piperidin 3 yl]methyl] 2 naphthamide; tert butyl[(1 benzylpiperidin 3 yl)methyl][2 (dimethylamino)ethyl]carbamate; tert butyl[(1 benzylpiperidin 3 yl)methyl][3 (dimethylamino)propyl]carbamate; tert butyl[2 (dimethylamino)ethyl](piperidin 3 ylmethyl)carbamate; tert butyl[3 (dimethylamino)propyl](piperidin 3 ylmethyl)carbamate; tert butyl[[1 (2,3 dihydro 1h inden 2 yl)piperidin 3 yl] methyl][3 (dimethylamino)propyl]carbamate; unclassified drug; unindexed drug; cholinesterase; cholinesterase inhibitor; protein binding; animal experiment; animal model; animal tissue; Article; binding affinity; Caco-2 cell line; cholinesterase inhibition; cognition; controlled study; crystal structure; drug structure; ex vivo study; female; Hep-G2 cell line; human; human cell; in vitro study; in vivo study; inhibition constant; learning; male; memory; mouse; nonhuman; rat; reaction optimization; scopolamine-induced amnesia; SH-SY5Y cell line; structure activity relation; animal; chemistry; drug design; kinetics; metabolism; molecular model; protein conformation; safety; thermodynamics; tissue distribution; X ray crystallography; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Crystallography, X-Ray; Drug Design; Female; Humans; Kinetics; Male; Mice; Models, Molecular; Protein Binding; Protein Conformation; Rats; Safety; Thermodynamics; Tissue Distribution