- Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation
-
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to
- Wu, Yong-Jin,Guernon, Jason,McClure, Andrea,Luo, Guanglin,Rajamani, Ramkumar,Ng, Alicia,Easton, Amy,Newton, Amy,Bourin, Clotilde,Parker, Dawn,Mosure, Kathleen,Barnaby, Omar,Soars, Matthew G.,Knox, Ronald J.,Matchett, Michele,Pieschl, Rick,Herrington, James,Chen, Ping,Sivarao,Bristow, Linda J.,Meanwell, Nicholas A.,Bronson, Joanne,Olson, Richard,Thompson, Lorin A.,Dzierba, Carolyn
-
-
Read Online
- HYDROXYPYRROLIDINE-SUBSTITUTED ARYLSULFONAMIDE COMPOUNDS WITH SELECTIVE ACTIVITY IN VOLTAGE-GATED SODIUM CHANNELS
-
Disclosed are compounds of Formula A, or a salt thereof: (A) Wherein "A1", R1, R2, R3, R6, and R7 are as defined herein, which compounds have properties for blocking Nav 1.7 ion channels fo
- -
-
-
- DIAMINO-ALKYLAMINO-LINKED ARYLSULFONAMIDE COMPOUNDS WITH SELECTIVE ACTIVITY IN VOLTAGE-GATED SODIUM CHANNELS
-
Disclosed are compounds of Formula A, or a salt thereof: Formula (A), wherein: Het, Q and R1A to R4A are defined herein, which compounds have properties for blocking Nav 1.7 ion channels found in peripheral and sympathetic
- -
-
-
- THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
-
The invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein the variables X, Y1-Y5, R1, R2, R3, R4, and Het have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.
- -
-
Paragraph 0306; 0307; 0308
(2018/04/26)
-
- BENZENESULFONAMIDE COMPOUNDS AND THEIR USE AS THERAPEUTIC AGENTS
-
This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy and/or epileptic seizure disorders.
- -
-
Paragraph 0684-0685
(2018/06/29)
-
- N1-PHENYLPROPANE-1,2-DIAMINE COMPOUNDS WITH SELECTIVE ACTIVITY IN VOLTAGE-GATED SODIUM CHANNELS
-
Disclosed are compounds of Formula A-1, or a salt thereof: Formula A-1, where J, K, Q and R1 are as defined herein, which compounds have properties for inhibiting sodium ion channels found in peripheral and sympathetic neurons. Also described are pharmace
- -
-
-
- The discovery of tetrahydropyridine analogs as hNav1.7 selective inhibitors for analgesia
-
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
- Wu, Wentao,Li, Zhixiang,Yang, Guangwen,Teng, Mingxing,Qin, Jian,Hu, Zhijing,Hou, Lijuan,Shen, Liang,Dong, Haiheng,Zhang, Yang,Li, Jian,Chen, Shuhui,Tian, Jingwei,Zhang, Jianzhao,Ye, Liang
-
supporting information
p. 2210 - 2215
(2017/04/27)
-
- Development of New Benzenesulfonamides As Potent and Selective Nav1.7 Inhibitors for the Treatment of Pain
-
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.
- Wu, Yong-Jin,Guernon, Jason,Shi, Jianliang,Ditta, Jonathan,Robbins, Kevin J.,Rajamani, Ramkumar,Easton, Amy,Newton, Amy,Bourin, Clotilde,Mosure, Kathleen,Soars, Matthew G.,Knox, Ronald J.,Matchett, Michele,Pieschl, Rick L.,Post-Munson, Debra J.,Wang, Shuya,Herrington, James,Graef, John,Newberry, Kimberly,Bristow, Linda J.,Meanwell, Nicholas A.,Olson, Richard,Thompson, Lorin A.,Dzierba, Carolyn
-
p. 2513 - 2525
(2017/04/03)
-
- BENZENESULFONAMIDE COMPOUNDS AND THEIR USE AS THERAPEUTIC AGENTS
-
This invention is directed to benzenesulfonamide compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of diseases or conditions associated with voltage-gated sodium channels, such as epilepsy.
- -
-
Page/Page column 121-122
(2017/12/18)
-
- BICYCLOAMINE-SUBSTITUTED-N-BENZENESULFONAMIDE COMPOUNDS WITH SELECTIVE ACTIVITY IN VOLTAGE-GATED SODIUM CHANNELS
-
Disclosed are compounds of Formula A-a, or a salt thereof: Where "B1" and "R1" through "R5" are as defined herein, which compounds have properties for blocking Nav 1.7 ion channels found in peripheral and sympathetic neurons. Also described are pharmaceutical formulations comprising the compounds of Formula A-a or their salts, and methods of treating neuropathic pain disorders using the same.
- -
-
-
- BICYCLOAMINE-SUBSTITUTED-N-BENZENESULFONAMIDE COMPOUNDS WITH SELECTIVE ACTIVITY IN VOLTAGE-GATED SODIUM CHANNELS
-
Disclosed are compounds of Formula (A-a), or a salt thereof, Where "B1" and "R1" through "R5" are as defined herein, which compounds have properties for blocking Nav 1.7 ion channels found in peripheral and sympathetic neurons. Also described are pharmaceutical formulations comprising the compounds of Formula (A-a) or their salts, and methods of treating neuropathic pain disorders using the same.
- -
-
-