Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Intepirdine Derivatives Possessing Dual 5HT6 Antagonism / HDAC6 Inhibitory Activity
Δημιουργός/Συγγραφέας:	Gkanas, Andreas Koutiva, Maria [EL] Κατσίλα, Θεοδώρα[EN] Katsila, Theodora Bafiti, Vivi Matsoukas, Minos-Timotheos Panagiotopoulos, Vasilios Bojarski, Andrzej J Gkouvitsas, Theodoros Moukas, Georgios Rassias, Gerasimos
Ημερομηνία:	2025-08-22
Γλώσσα:	Αγγλικά
ISSN:	0947-6539 1521-3765
DOI:	10.1002/chem.202500025
Άλλο:	40842345
Περίληψη:	Alzheimer's Disease (AD) impacts significantly the quality of life of people aged over 65 years old, while millions more suffer from other types of dementia, yet no effective drugs exist. The few approved drugs in this area address mostly the associated symptoms, while several selective agents acting on promising targets have failed in clinical trials. The complexity of neurodegenerative diseases has prompted multitargeting ligands as the new paradigm, where more than one biological mechanism may be perturbed synergistically. In this context, we explored the design and synthesis of dual 5-ΗΤ6 antagonists / HDAC6 inhibitors since these actions have been individually demonstrated to elicit cognitive-enhancing effects. Prototypes with this dual action on a GPCR and an enzyme were designed and synthesized by tethering an aryl-hydroxamic acid unit, an established pharmacophore for HDAC6 inhibition, to the piperazine of intepirdine, a potent 5-ΗΤ6 antagonist. A new gram-scale synthesis of intepirdine was developed followed by attaching different types of arylhydroxamic acids. Derivative RG-283AG emerged to possess sub-micromolar potency toward HDAC6 inhibition (IC50 0.54 μμ), nanomolar affinity (Ki 0.7 nM) for 5-HT6 receptor and favorable BBB penetration capacity, thus constituting the first example of a dual-acting 5-ΗΤ6 / HDAC6 ligand with potential cognitive-enhancing properties.
Τίτλος πηγής δημοσίευσης:	Chemistry (Weinheim an der Bergstrasse, Germany)
Θεματική Κατηγορία:	[EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry [EL] Θεραπευτική. Φαρμακολογία[EN] Therapeutics.Pharmacology [EL] Νευροεπιστήμη. Βιολογική ψυχιατρική. Νευροψυχιατρική[EN] Neurosciences. Biological psychiatry. Neuropsychiatry [EL] Φυσιολογία[EN] Physiology [EL] Χημική Βιολογία[EN] Chemical Biology
Λέξεις-Κλειδιά:	5HT6 antagonists Alzheimer Disease Buchwald‐Hartwig N‐arylation HDAC6 inhibitors T3P amide synthesis cognitive decline dementia hydroxamic acids intepirdine multi‐targeting directed ligands quinoline Ullmann‐type coupling sulfide oxidation to sulfone
Χρηματοδότης:	Research and Technology-Hellas
Χρηματοδοτικό πρόγραμμα:	T2EDK-04436
Κάτοχος πνευματικών δικαιωμάτων:	© 2025 The Author(s). Chemistry – A European Journal published by Wiley-VCH GmbH
Όροι και προϋποθέσεις δικαιωμάτων:	This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.1002/chem.202500025
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο