title: The discovery of tetrahydropyridine analogs as hNav1.7 selective inhibitors for analgesia.
abstract: hNav1.7 small molecular inhibitors have attracted lots of attention by its unique analgesic effect. Herein, we report the design and synthesis of a novel series of tetrahydropyridine analogs as hNav1.7 inhibitors for analgesia. Detail structural-activity relationship (SAR) studies were undertaken towards improving hNav1.7 activity, in vitro ADME, and in vivo PK profiles. These efforts resulted in the identification of compound (-)-15h, a highly potent and selective hNav1.7 inhibitor with good ADME and PK profiles.
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Wu
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Guangwen
authors.initials: G
authors.lastname: Yang
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Teng
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Qin
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Zhijing
authors.initials: Z
authors.lastname: Hu
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Hou
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shen
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Haiheng
authors.initials: H
authors.lastname: Dong
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China. Electronic address: zhang_yang@wuxiapptec.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, People's Republic of China. Electronic address: Tianjingwei@luye.com.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Tian
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, People's Republic of China.
authors.forename: Jianzhao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ye
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011725:Pyridines; D013449:Sulfonamides; D061567:Voltage-Gated Sodium Channel Blockers; D065729:Cytochrome P-450 CYP2C9; C023666:pyridine
keywords: Analgesia; Pain; Tetrahydropyridine; Voltage-gated sodium channel; hNav1.7