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Bioorg Med Chem Lett. 2015 Feb 1;25(3):581-6. doi: 10.1016/j.bmcl.2014.12.019. Epub 2014 Dec 13.

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

Author information

1
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany. Electronic address: doris.riether@boehringer-ingelheim.com.
2
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
3
Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
4
Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
5
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany.

Abstract

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.

KEYWORDS:

Cannabinoid receptor 2 (CB2); Metabolic stability; Pharmacokinetic properties; Proline; Solubility

PMID:
25556092
DOI:
10.1016/j.bmcl.2014.12.019
[Indexed for MEDLINE]

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