Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine) and related analogs as potential therapeutic agents for Alzheimer's disease.
A series of novel N-(4-pyridinyl)-1H-indol-1-amines and other heteroaryl analogs was synthesized and evaluated in tests to determine potential utility for the treatment of Alzheimer's disease. From these compounds, N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine, 4c) was selected for clinical development based on in-depth biological evaluation. In addition to cholinomimetic properties based initially on in vitro inhibition of [3H]quinuclidinyl benzilate binding, in vivo reversal of scopolamine-induced behavioral deficits, and subsequently on other results, 4c also displayed enhancement of adrenergic mechanisms as evidenced in vitro by inhibition of [3H] clonidine binding and synaptosomal biogenic amine uptake, and in vivo by reversal of tetrabenazine-induced ptosis. The synthesis, structure-activity relationships for this series, and the biological profile of 4c are reported.
Klein
J T
JT
Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey 08876, USA.
Davis
L
L
Olsen
G E
GE
Wong
G S
GS
Huger
F P
FP
Smith
C P
CP
Petko
W W
WW
Cornfeldt
M
M
Wilker
J C
JC
Blitzer
R D
RD
Landau
E
E
Haroutunian
V
V
Martin
L L
LL
Effland
R C
RC
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001679:Biogenic Amines / Q000037:antagonists & inhibitors / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D001679:Biogenic Amines; D007211:Indoles; D010276:Parasympatholytics; D011725:Pyridines; C074872:besipirdine