Journal of Medicinal Chemistry p. 5049 - 5062 (2019)
Update date:2022-09-26
Topics:
Tseng, Chih-Chung
Baillie, Gemma
Donvito, Giulia
Mustafa, Mohammed A.
Juola, Sophie E.
Zanato, Chiara
Massarenti, Chiara
Dall'Angelo, Sergio
Harrison, William T. A.
Lichtman, Aron H.
Ross, Ruth A.
Zanda, Matteo
Greig, Iain R.
The first generation of CB1 positive allosteric modulators (e.g., ZCZ011) featured a 3-nitroalkyl-2-phenyl-indole structure. Although a small number of drugs include the nitro group, it is generally not regarded as being "drug-like", and this is particularly true for aliphatic nitro groups. There are very few case studies where an appropriate bioisostere replaced a nitro group that had a direct role in binding. This may be indicative of the difficulty of replicating its binding interactions. Herein, we report the design and synthesis of ligands targeting the allosteric binding site on the CB1 cannabinoid receptor, in which a CF3 group successfully replaced the aliphatic NO2. In general, the CF3-bearing compounds were more potent than their NO2 equivalents and also showed improved in vitro metabolic stability. The CF3 analogue (1) with the best balance of properties was selected for further pharmacological evaluation. Pilot in vivo studies showed that (±)-1 has similar activity to (±)-ZCZ011, with both showing promising efficacy in a mouse model of neuropathic pain.
View MoreNanjing Zelang Medical Technology Co. Ltd
Contact:86-25-83063290/13770714480
Address:Ganjiabian 108# 01 Unit,701-702 room,Yao Hua Street,Qixia District,Nanjing,Jiangsu,China
Jinan Hongfangde Pharmatech Co.,Ltd
Contact:86-531-88870908
Address:F Bldg. West Unit North Area of Univ. Tech. Garden Xinyu Rd. Jinan New & High Tech Industry Development Zone Shandong, China
Nanjing Chemzam Pharmtech Co., Ltd.
Contact:+86-25-86462165,+86-13915979898
Address:C5-1,6 Maiyue Road,Maigaoqiao,Nanjing,Jiangsu,China
Chuzhou Baiao Biologhy S&T Co., Ltd.
Contact:+86-25-83212599;+86-25-83212699 13705185959
Address:Room 905, Tianzheng International Platza, No.399, Zhongyang Road ,Nanjing, Jiangsu Province, China
Hubei Sky Lake Chemical Co., Ltd.
Contact:+86-27-87385545
Address:Te-2, Xijiao Chemical Park, Yuekou Town, Tianmen, Hubei, China.
Doi:10.1080/00397919608003769
(1996)Doi:10.1055/s-2006-948184
(2006)Doi:10.1248/cpb.40.661
(1992)Doi:10.1016/S0040-4020(01)82133-5
(1966)Doi:10.1002/mrc.1260230205
(1985)Doi:10.1021/om0606892
(2006)