Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds.

Autor: Riether D; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany. Electronic address: doris.riether@boehringer-ingelheim.com., Zindell R; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA., Wu L; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA., Betageri R; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA., Jenkins JE; Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom., Khor S; Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom., Berry AK; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA., Hickey ER; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA., Ermann M; Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom., Albrecht C; Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany., Ceci A; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany., Gemkow MJ; Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany., Nagaraja NV; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA., Romig H; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany., Sauer A; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany., Thomson DS; Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Feb 01; Vol. 25 (3), pp. 581-6. Date of Electronic Publication: 2014 Dec 13.
DOI: 10.1016/j.bmcl.2014.12.019
Abstrakt: Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.
(Copyright © 2014 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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