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J Med Chem. 2017 Mar 23;60(6):2526-2551. doi: 10.1021/acs.jmedchem.6b01868. Epub 2017 Mar 13.

Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity in Vivo.

Author information

1
Dr. August Wolff GmbH & Co. KG Arzneimittel , Sudbrackstraße 56, D-33611 Bielefeld, Germany.
2
Mercachem , Kerkenbos 1013, NL-6546 BB Nijmegen, The Netherlands.
3
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster , Correnstraße 48, D-48149 Münster, Germany.
4
Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Universität Münster , D-48149 Münster, Germany.
5
Klinik für Hautkrankheiten, Universitätsklinikium Münster , Von-Esmarch-Straße 58, D-48149 Münster, Germany.
6
Kompetenzzentrum chronischer Pruritus (KCP), Universitätsklinikium Münster , Von-Esmarch-Straße 58, D-48149 Münster, Germany.
7
Eurofins Panlabs Taiwan, Ltd. , 158 Li-Teh Road, Peitou, Taipei 11259, Taiwan.

Abstract

In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [35S]GTPγS assay, and high selectivity over μ, δ, σ1, and σ2 receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (Ki = 0.63 nM) and highly selective κ agonist (EC50 = 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.

PMID:
28218838
DOI:
10.1021/acs.jmedchem.6b01868
[Indexed for MEDLINE]

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