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

被引：11

作者：

Riether, Doris ^{[2
]}

Zindell, Renee ^{[1
]}

Wu, Lifen ^{[1
]}

Betageri, Raj ^{[1
]}

Jenkins, James E. ^{[3
]}

Khor, Someina ^{[3
]}

Berry, Angela K. ^{[1
]}

Hickey, Eugene R. ^{[1
]}

Ermann, Monika ^{[3
]}

Albrecht, Claudia ^{[4
]}

Ceci, Angelo ^{[2
]}

Gemkow, Mark J. ^{[4
]}

Nagaraja, Nelamangala V. ^{[1
]}

Romig, Helmut ^{[2
]}

Sauer, Achim ^{[2
]}

Thomson, David S. ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA

[2] Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach An Der Riss, Germany

[3] Evotec UK Ltd, Abingdon OX14 4RZ, Oxon, England

[4] Evotec AG, D-22419 Hamburg, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 03期

关键词：

Cannabinoid receptor 2 (CB2); Proline; Metabolic stability; Solubility; Pharmacokinetic properties; CANNABINOID RECEPTOR; NEUROPATHIC PAIN; EXPRESSION; EFFICACY; AFFINITY; LIGANDS; SYSTEM;

D O I：

10.1016/j.bmcl.2014.12.019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：581 / 586

页数：6

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