Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group.

Saitoh, T ; Seki, K ; et al.

In: Bioorganic & medicinal chemistry letters, Jg. 30 (2020-02-01), Heft 3, S. 126893

academicJournal

The morphinan-type orexin 1 receptor (OX 1 R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX 1 R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX 1 R antagonistic activity. The assay results showed the interesting relationship between the OX 1 R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX 1 R antagonistic activity (K i = 14.8 nM).

Titel:	Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group.
Autor/in / Beteiligte Person:	Saitoh, T ; Seki, K ; Nakajima, R ; Yamamoto, N ; Kutsumura, N ; Nagumo, Y ; Irukayama-Tomobe, Y ; Ogawa, Y ; Ishikawa, Y ; Yanagisawa, M ; Nagase, H
Zeitschrift:	Bioorganic & medicinal chemistry letters, Jg. 30 (2020-02-01), Heft 3, S. 126893
Veröffentlichung:	Oxford : Elsevier Science Ltd ; <i>Original Publication</i>: Oxford ; New York : Pergamon Press, c1991-, 2020
Medientyp:	academicJournal
ISSN:	1464-3405 (electronic)
DOI:	10.1016/j.bmcl.2019.126893
Schlagwort:	Amines chemistry Humans Kinetics Morphinans metabolism Orexin Receptor Antagonists chemical synthesis Orexin Receptor Antagonists metabolism Orexin Receptors metabolism Structure-Activity Relationship Sulfonamides metabolism Morphinans chemistry Orexin Receptor Antagonists chemistry Orexin Receptors chemistry Sulfonamides chemistry
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Bioorg Med Chem Lett] 2020 Feb 01; Vol. 30 (3), pp. 126893. <i>Date of Electronic Publication: </i>2019 Dec 17. MeSH Terms: Morphinans / chemistry ; Orexin Receptor Antagonists / chemistry ; Orexin Receptors / chemistry ; Sulfonamides / chemistry ; Amines / chemistry ; Humans ; Kinetics ; Morphinans / metabolism ; Orexin Receptor Antagonists / chemical synthesis ; Orexin Receptor Antagonists / metabolism ; Orexin Receptors / metabolism ; Structure-Activity Relationship ; Sulfonamides / metabolism Contributed Indexing: Keywords: Nalfurafine; Orexin; Ring removal; Substituent effect; YNT-707 Substance Nomenclature: 0 (Amines) ; 0 (Morphinans) ; 0 (Orexin Receptor Antagonists) ; 0 (Orexin Receptors) ; 0 (Sulfonamides) ; 0 (YNT-707) Entry Date(s): Date Created: 20191228 Date Completed: 20210128 Latest Revision: 20210128 Update Code: 20231215

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