Bioorganic and Medicinal Chemistry Letters, volume 22, issue 1, pages 421-426

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

Satheesh Babu Ravula 1
Jinghua Yu 1
Joe A Tran 1
Melissa Arellano 1
Fabio C. Tucci 1
Wilna J. Moree 1
Bin Feng Li 1
Robert E. Petroski 1
Jianyun Wen 1
Siobhan Malany 1
SAMUEL R.J. HOARE 1
Ajay Madan 1
Paul D Crowe 1
Graham Beaton 1
Show full list: 14 authors
1
 
Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA
Publication typeJournal Article
Publication date2012-01-01
scimago Q2
wos Q2
SJR0.508
CiteScore5.7
Impact factor2.5
ISSN0960894X, 14643405
Organic Chemistry
Drug Discovery
Biochemistry
Molecular Biology
Pharmaceutical Science
Clinical Biochemistry
Molecular Medicine
Abstract
The structure–activity relationships of 2-(piperidin-3-yl)-1 H -benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1 H -benzimidazoles are described. In the lead optimization process, the p K a and/or log P 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)-1 H -benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1 H -benzimidazoles are described. In the lead optimization process, the p K a and/or log P 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.
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