title: SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists.
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.
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: shuwen_he@merck.com.
authors.forename: Shuwen
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Sharon X
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.initials: KL
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.lastname: Morissette
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Sylvia
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.lastname: Li
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.initials: BB
authors.lastname: Zhang
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
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authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D002243:Carbolines; C000611970:MK-4256; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3
keywords: Antagonist; SAR; Somatostatin receptor subtype 3; Tetrahydro-β-carboline; hERG