title: 2-Fluoro-4-pyridinylmethyl analogues of linopirdine as orally active acetylcholine release-enhancing agents with good efficacy and duration of action.
abstract: In an effort to improve the pharmacokinetic and pharmacodynamic properties of the cognition-enhancer linopirdine (DuP 996), a number of core structure analogues were prepared in which the 4-pyridyl pendant group was systematically replaced with 2-fluoro-4-pyridyl. This strategy resulted in the discovery of several compounds with improved activity in acetylcholine (ACh) release-enhancing assays, in vitro and in vivo. The most effective compound resulting from these studies, 10, 10-bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (9), is between 10 and 20 times more potent than linopirdine in increasing extracellular hippocampal ACh levels in the rat with a minimum effective dose of 1 mg/kg. In addition to superior potency, 9 possesses an improved pharmacokinetic profile compared to that of linopirdine. The half-life of 9 (2 h) in rats is 4-fold greater than that of linopirdine (0.5 h), and it showed a 6-fold improvement in brain-plasma distribution over linopirdine. On the basis of its pharmacologic, pharmacokinetic, absorption, and distribution properties, 9 (DMP543) has been advanced for clinical evaluation as a potential palliative therapeutic for treatment of Alzheimer's disease.
authors.affiliation: The DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Earl
authors.forename: R
authors.initials: R
authors.lastname: Zaczek
authors.forename: C A
authors.initials: CA
authors.lastname: Teleha
authors.forename: B N
authors.initials: BN
authors.lastname: Fisher
authors.forename: C M
authors.initials: CM
authors.lastname: Maciag
authors.forename: M E
authors.initials: ME
authors.lastname: Marynowski
authors.forename: A R
authors.initials: AR
authors.lastname: Logue
authors.forename: S W
authors.initials: SW
authors.lastname: Tam
authors.forename: W J
authors.initials: WJ
authors.lastname: Tinker
authors.forename: S M
authors.initials: SM
authors.lastname: Huang
authors.forename: R J
authors.initials: RJ
authors.lastname: Chorvat
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000873:Anthracenes; D007211:Indoles; D018697:Nootropic Agents; D011725:Pyridines; C112296:DMP 543; C061017:linopirdine; D000109:Acetylcholine