3409-21-0Relevant academic research and scientific papers
Selectivity profiling of novel indene H1-antihistamines for the treatment of insomnia
Li, Bin-Feng,Moree, Wilna J.,Yu, Jinghua,Coon, Timothy,Zamani-Kord, Said,Malany, Siobhan,Jalali, Kayvon,Wen, Jianyun,Wang, Hua,Yang, Chun,Hoare, Samuel R.J.,Petroski, Robert E.,Madan, Ajay,Crowe, Paul D.,Beaton, Graham
scheme or table, p. 2629 - 2633 (2010/06/19)
A series of indene analogs of the H1-antihistamine (-)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H1-antihistamines with desirable selectivity over CYP enzymes, the M1 muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.
Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia
Moree, Wilna J.,Li, Bin-Feng,Jovic, Florence,Coon, Timothy,Yu, Jinghua,Gross, Raymond S.,Tucci, Fabio,Marinkovic, Dragan,Zamani-Kord, Said,Malany, Siobhan,Bradbury, Margaret J.,Hernandez, Lisa M.,O'Brien, Zhihong,Wen, Jianyun,Wang, Hua,Hoare, Samuel R. J.,Petroski, Robert E.,Sacaan, Aida,Madan, Ajay,Crowe, Paul D.,Beaton, Graham
supporting information; experimental part, p. 5307 - 5310 (2010/06/13)
Analogues of the known H1-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
SLEEP INDUCING COMPOUNDS AND METHODS RELATING THERETO
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Page/Page column 32-33, (2010/02/14)
Compounds having the following structure: (I) including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein R1, R2a, R2b, R3, R4, R5a, R5b, L1, L2 and n are as defined herein. Pharmaceutical compositions containing one or more compounds of structure (I), as well as methods relating to the use thereof, including methods for treating insomnia, inducing sleep or inducing sedation or hypnosis, are also disclosed.
Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists
B?hme, Thomas M.,Keim, Christine,Kreutzmann, Kai,Linder, Matthias,Dingermann, Theo,Dannhardt, Gerd,Mutschler, Ernst,Lambrecht, Günter
, p. 856 - 867 (2007/10/03)
A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H1 receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M1-M5) and for human histamine H1 receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [3H]N-methylscopolamine ([3H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M2 receptors ((S)-dimethindene: pKi = 7.52; (-)-19: pKi = 7.37) with an improved selectivity pattern ((S)-dimethindene: M2/M1 = 6-fold, M2/M3 = 5-fold, M2/M4 = 10-fold, M2/M5 = 25-fold; (-)-19: M2/M1 = 36-fold, M2/M3 = 96-fold, M2/M4 = 42-fold, M2/M5 = 275-fold). In addition, compound (-)-19 showed 35-fold lower affinity at histamine H1 receptors (pKi = 5.61) than (S)-dimethindene (pKi = 7.16). Another interesting compound is the fluoroethyl derivative 20 (pKi/M2 = 7.49), which also exhibits a higher M2 selectivity (M2/M1 = 19-fold; M2/M3 = 22-fold; M2/M4 13-fold; M2/M5 = 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity for histamine H1 receptors (pKi = 8.14). The compound with the highest affinity for M2 receptors (pKi = 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for M2 receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that blockade of muscarinic M2 receptors in the brain is a viable mechanism by which to produce improved cognition. This second-generation dimethindene analogue might also be the starting point for the development of M2-selective muscarinic antagonists useful for quantifying M2 receptors in the central nervous system with positron emission tomography imaging.
