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Bioorg Med Chem Lett. 2015 Feb 1;25(3):587-92. doi: 10.1016/j.bmcl.2014.12.031. Epub 2014 Dec 17.

Selective CB2 receptor agonists. Part 3: the optimization of a piperidine-based series that demonstrated efficacy in an in vivo neuropathic pain model.

Author information

1
Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
2
Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
3
Boehringer Ingelheim Pharma GmbH&Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany.

Abstract

A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.

KEYWORDS:

CB1; CB2; Cannabinoid receptor; Metabolic stability; Piperidine; Solubility

PMID:
25575658
DOI:
10.1016/j.bmcl.2014.12.031
[Indexed for MEDLINE]

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