- Discovery of Arylsulfonamide Nav1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile
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The voltage-gated sodium channel Nav1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Nav1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Nav1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Nav1.7 inhibitors to afford improved selectivity over Nav1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report in vitro-in vivo correlations from Nav1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound 19 with potency against Nav1.7, selectivity over Nav1.5 and Nav1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.
- Ballard, Jeanine E.,Brunskill, Andrew P. J.,Burgey, Christopher S.,Clements, Michelle,Daley, Christopher,Greshock, Thomas J.,Houghton, Andrea K.,Jovanovska, Aneta,Kelly, Michael J.,Klein, Rebecca,Kraus, Richard L.,Layton, Mark E.,Li, Yuxing,Peng, Xuanjia,Pero, Joseph E.,Roecker, Anthony J.,Sun, Haiyan,Wang, Deping,Wang, Xiu,Zhao, Fuqiang
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supporting information
p. 1038 - 1049
(2021/06/28)
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- N1-PHENYLPROPANE-1,2-DIAMINE COMPOUNDS WITH SELECTIVE ACTIVITY IN VOLTAGE-GATED SODIUM CHANNELS
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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
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Paragraph 0113
(2017/10/30)
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- COMPOUNDS FOR USE IN IMAGING, DIAGNOSING, AND/OR TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM OR OF TUMORS
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This invention relates to novel compounds suitable for labelling or already labelled by 18F, methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds
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Page/Page column 68-69; 70
(2009/05/28)
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- 3-(2-Aminoalkyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl) -6-methyluracils as orally bioavailable antagonists of the human gonadotropin releasing hormone receptor
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Uracils possessing N-3 side chains derived from various amino alcohols were designed and synthesized as potent human gonadotropin releasing hormone receptor antagonists. The compounds herein presented displayed superior metabolic stability than their pred
- Tucci, Fabio C.,Zhu, Yun-Fei,Guo, Zhiqiang,Gross, Timothy D.,Connors Jr., Patrick J.,Gao, Yinghong,Rowbottom, Martin W.,Struthers, R. Scott,Reinhart, Greg J.,Xie, Qiu,Chen, Ta Kung,Bozigian, Haig,Bonneville, Anne L. Killam,Fisher, Andrew,Jin, Liping,Saunders, John,Chen, Chen
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p. 3483 - 3486
(2007/10/03)
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- A practical protocol for chemoselective N-methylation of vicinal amino alcohols
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A practical method for the chemoselective N-methylation of vicinal amino alcohols is described. (C) 2000 Elsevier Science Ltd.
- Vidyasagar Reddy,Venkat Rao,Sreevani,Iyengar
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p. 949 - 951
(2007/10/03)
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