title: 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.
abstract: 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.
authors.affiliation: Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey 08876, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Klein
authors.forename: L
authors.initials: L
authors.lastname: Davis
authors.forename: G E
authors.initials: GE
authors.lastname: Olsen
authors.forename: G S
authors.initials: GS
authors.lastname: Wong
authors.forename: F P
authors.initials: FP
authors.lastname: Huger
authors.forename: C P
authors.initials: CP
authors.lastname: Smith
authors.forename: W W
authors.initials: WW
authors.lastname: Petko
authors.forename: M
authors.initials: M
authors.lastname: Cornfeldt
authors.forename: J C
authors.initials: JC
authors.lastname: Wilker
authors.forename: R D
authors.initials: RD
authors.lastname: Blitzer
authors.forename: E
authors.initials: E
authors.lastname: Landau
authors.forename: V
authors.initials: V
authors.lastname: Haroutunian
authors.forename: L L
authors.initials: LL
authors.lastname: Martin
authors.forename: R C
authors.initials: RC
authors.lastname: Effland
mesh_terms: 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
chemical_list: D001679:Biogenic Amines; D007211:Indoles; D010276:Parasympatholytics; D011725:Pyridines; C074872:besipirdine