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SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Mar 15; Vol. 26 (6), pp. 1529-1535. Date of Electronic Publication: 2016 Feb 10. - Publication Year :
- 2016
-
Abstract
- MK-4256, a tetrahydro-β-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-β-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 26
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26898814
- Full Text :
- https://doi.org/10.1016/j.bmcl.2016.02.022