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
1
Neurocrine Biosciences, 12780 El Camino Real, San Diego, CA 92130, USA
|
Publication type: Journal Article
Publication date: 2012-01-01
scimago Q2
wos Q2
SJR: 0.472
CiteScore: 5.1
Impact factor: 2.2
ISSN: 0960894X, 14643405
PubMed ID:
22153347
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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17
Total citations:
17
Citations from 2024:
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(11.76%)
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GOST
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Ravula S. B. et al. 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 // Bioorganic and Medicinal Chemistry Letters. 2012. Vol. 22. No. 1. pp. 421-426.
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Ravula S. B., Yu J., Tran J. A., Arellano M., Tucci F. C., Moree W. J., Li B. F., Petroski R. E., Wen J., Malany S., HOARE S. R., Madan A., Crowe P. D., Beaton G. 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 // Bioorganic and Medicinal Chemistry Letters. 2012. Vol. 22. No. 1. pp. 421-426.
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TY - JOUR
DO - 10.1016/j.bmcl.2011.10.115
UR - https://doi.org/10.1016/j.bmcl.2011.10.115
TI - 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
T2 - Bioorganic and Medicinal Chemistry Letters
AU - Ravula, Satheesh Babu
AU - Yu, Jinghua
AU - Tran, Joe A
AU - Arellano, Melissa
AU - Tucci, Fabio C.
AU - Moree, Wilna J.
AU - Li, Bin Feng
AU - Petroski, Robert E.
AU - Wen, Jianyun
AU - Malany, Siobhan
AU - HOARE, SAMUEL R.J.
AU - Madan, Ajay
AU - Crowe, Paul D
AU - Beaton, Graham
PY - 2012
DA - 2012/01/01
PB - Elsevier
SP - 421-426
IS - 1
VL - 22
PMID - 22153347
SN - 0960-894X
SN - 1464-3405
ER -
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@article{2012_Ravula,
author = {Satheesh Babu Ravula and Jinghua Yu and Joe A Tran and Melissa Arellano and Fabio C. Tucci and Wilna J. Moree and Bin Feng Li and Robert E. Petroski and Jianyun Wen and Siobhan Malany and SAMUEL R.J. HOARE and Ajay Madan and Paul D Crowe and Graham Beaton},
title = {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},
journal = {Bioorganic and Medicinal Chemistry Letters},
year = {2012},
volume = {22},
publisher = {Elsevier},
month = {jan},
url = {https://doi.org/10.1016/j.bmcl.2011.10.115},
number = {1},
pages = {421--426},
doi = {10.1016/j.bmcl.2011.10.115}
}
Cite this
MLA
Copy
Ravula, Satheesh Babu, et al. “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.” Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 1, Jan. 2012, pp. 421-426. https://doi.org/10.1016/j.bmcl.2011.10.115.