145508-75-4Relevant academic research and scientific papers
Combinations of D4 dopamine receptor antagonists with acetylcholine esterase inhibitors
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, (2008/06/13)
The present invention relates to a method of treating dementia or cognitive deficits associated with Alzheimer's Disease or Parkinson's Disease in a mammal, including a human, by administering to the mammal a D4 dopamine receptor antagonist in combination with an acetylcholine esterase inhibitor. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a D4 dopamine receptor antagonist and an acetylcholine esterase inhibitor.
BENZISOXAZOLE COMPOUND AND USE THEREOF
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, (2008/06/13)
A benzisoxazole compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein, when the bond (a) between the 2- and 3-positions represents a single bond, Rarepresents the group (II) (wherein R represents hydrogen, alkyl, alkenyl, cycloalkylalkyl, cycloalkylalkenyl, phenylalkenyl, naphthylalkyl or naphthylalkenyl; A represents linear or branched alkylene; and n represents 1, 2 or 3) and Rbrepresents oxygen, or alternatively when the bond (a) between the 2- and 3-positions represents a double bond, Rais absent; Rbrepresents either the group (III), wherein each symbol is as defined above, or the group (IV), wherein E represents oxygen or sulfur, and R, A and n are each as defined above; and R1, R2, R3 and R4 are each as defined in the specification. This compound has a centroselective acetylcholine esterase inhibiting activity and/or a potent affinity for sigma receptor.
Novel benzisoxazole derivatives as potent and selective inhibitors of acetylcholinesterase
Villalobos,Blake,Biggers,Butler,Chapin,Chen,Ives,Jones,Liston,Nagel,Nason,Nielsen,Shalaby,White
, p. 2721 - 2734 (2007/10/02)
A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3- methyl-1,2-benzisoxazoles with an iodo piperidine derivative as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl- over butyrylcholinesterase, in excess of 3 orders of magnitude. N-acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease.
