title: Discovery of novel substituted octahydropyrrolo[3,4-c]pyrroles as dual orexin receptor antagonists for insomnia treatment.
abstract: A series of octahydropyrrolo[3,4-c]pyrroles were synthesized and evaluated by orexin 1 and 2 receptor (OX1 & 2R) antagonists assays. Compound 14l with potent OXR antagonist activity and suitable pharmacokinetic behavior was chosen to be investigated in an EEG study, which demonstrated effects of sleep promotion comparable to Suvorexant. Furthermore, the di-fluro substituted analogs exhibited reduced hERG inhibition while maintaining moderate potency.
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Songliang
authors.initials: S
authors.lastname: Wu
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., o.8, 67 Libing Road, Shanghai 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Hou
authors.affiliation: Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., o.8, 67 Libing Road, Shanghai 201203, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., o.8, 67 Libing Road, Shanghai 201203, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China. Electronic address: he_haiying@wuxiapptec.com.
authors.forename: Haiying
authors.initials: H
authors.lastname: He
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Luo
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Yuhe
authors.initials: Y
authors.lastname: Wang
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Shi
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shen
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Cao
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., o.8, 67 Libing Road, Shanghai 201203, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lv
authors.affiliation: Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., o.8, 67 Libing Road, Shanghai 201203, China. Electronic address: jiongl@haiyanpharma.com.
authors.forename: Jiong
authors.initials: J
authors.lastname: Lan
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: WuXi AppTec (Shanghai) Co. Ltd., 288 Fute Zhong Road, Shanghai 200131, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004569:Electroencephalography; D006801:Humans; D008297:Male; D000068796:Orexin Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy* / Q000503:physiopathology; D013329:Structure-Activity Relationship
chemical_list: D000068796:Orexin Receptor Antagonists; D011758:Pyrroles
keywords: Antagonists; Insomnia; Octahydropyrrolo[3,4-c]pyrroles; Orexin receptors