170491-63-1Relevant articles and documents
Discovery of Arylsulfonamide Nav1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile
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
supporting information, p. 1038 - 1049 (2021/06/28)
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.
Inexpensive multigram-scale synthesis of cyclic enamines and 3-N spirocyclopropyl systems
Kumar, Pratik,Zainul, Omar,Laughlin, Scott T.
supporting information, p. 652 - 656 (2018/02/07)
Cyclic enamines are important synthons for many synthetic and pharmacological targets. Here, we report an inexpensive, catalyst-free, multigram-scale synthesis for cyclic enamines with exocyclic double bonds and four- to seven-membered rings. This strategy is more conducive to scale up, permissive of functionalization around the cyclic system, and less sensitive to the nature of the N-protecting group than previously-described methods for cyclic enamine synthesis. Further, we explore application of these enamines to the synthesis of highly-strained spirocyclic 3N-cyclopropyl scaffolds.
As hepatitis c inhibitor spiro compound and its use in medicine
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Paragraph 0814; 1804; 1805, (2017/12/28)
The invention provides a spiro compound serving as a hepatitis c inhibitor and application thereof in a medicine. The compound is a compound as shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, an aquo-complex, a solvate, a metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in the formula (I). The invention also provides a pharmaceutical composition containing the compound, application of the compound and the pharmaceutical composition in inhibition of HCV (Hepatitis C Virus) copy and HCV virus protein, as well as the application of the compound and the pharmaceutical composition in prevention, handling, treatment or relieving of HCV infection or hepatitis c disease for a patient. The formula I is as shown in the specification.