Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease.
Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere.
Sterling
Jeffrey
J
Research and Development Division, Teva Pharmaceutical Industries, Abic, P.O. Box 8077, Netanya 42504, Israel. jeffrey.sterling@teva.co.il
Herzig
Yaacov
Y
Goren
Tamar
T
Finkelstein
Nina
N
Lerner
David
D
Goldenberg
Willy
W
Miskolczi
Istvan
I
Molnar
Sandor
S
Rantal
Ferenc
F
Tamas
Tivadar
T
Toth
Gyorgy
G
Zagyva
Adela
A
Zekany
Andras
A
Finberg
John
J
Lavian
Gila
G
Gross
Aviva
A
Friedman
Rachel
R
Razin
Michal
M
Huang
Wei
W
Krais
Boris
B
Chorev
Michael
M
Youdim
Moussa B
MB
Weinstock
Marta
M
D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry*; D011437:Propylamines / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; D011437:Propylamines; C009054:propargylamine; C029261:phenethylamine; D010293:Pargyline; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase