2014 Dec 17. pii: S0960-894X(14)01328-6. doi: 10.1016/j.bmcl.2014.12.031. [Epub ahead of print]
Selective CB2 receptor agonists. Part 3: The optimization of a piperidine-based series that demonstrated efficacy in an in vivo neuropathic pain model.
Bartolozzi A1, Cirillo PF1, Berry AK1, Hickey ER1, Thomson DS1, Wu L1, Zindell R1, Albrecht C2, Ceci A3, Gemkow MJ2, Nagaraja NV1, Romig H3, Sauer A3, Riether D3.
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.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Copyright © 2014 Elsevier Ltd. All rights reserved.
KEYWORDS:
CB1; CB2; Cannabinoid receptor; Metabolic stability; Piperidine; Solubility
- PMID:
- 25575658
- [PubMed – as supplied by publisher]
