Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: Identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H1-antihistamines for insomnia

The structure–activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pKa and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidin...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.421-426
Hauptverfasser: Ravula, Satheesh Babu, Yu, Jinghua, Tran, Joe A., Arellano, Melissa, Tucci, Fabio C., Moree, Wilna J., Li, Bin-Feng, Petroski, Robert E., Wen, Jianyun, Malany, Siobhan, Hoare, Samuel R.J., Madan, Ajay, Crowe, Paul D., Beaton, Graham
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Sprache:eng
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Zusammenfassung:The structure–activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pKa and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics. The structure–activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pKa and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.10.115