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Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Sodium Channel Modulators and Their Method of Use Benjamin E. Blass* Temple University School of Pharmacy, Moulder Center for Drug Discovery Research, Philadelphia, Pennsylvania 19140, United States
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Important Compound Classes.
Each R4 is independently selected from hydroxy, acyl, acyloxy, amino, thio, halogen, cyano, optionally substituted C1−C6 alkyl, optionally substituted C1−C6 haloalkyl, optionally substituted −OC1−C6 alkyl, optionally substituted −OC1−C6 haloalkyl, optionally substituted C1−C6 alkyl amino, optionally substituted C1−C6 dialkyl amino, optionally substituted C3−C7 cycloalkyl, optionally substituted C2−C12 heterocyclyl, optionally substituted aryl; or optionally substituted aryloxy; R5 is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; and n is an integer selected from 0, 1, and 2. Key Structures.
Title. Therapeutic compounds and uses thereof Patent Application Number. WO 2019/126842 A1 Publication Date. July 4th, 2019 Priority Application. AU 2017905204 Priority Date. December 27th, 2017 Inventors. Hollis, C.; Kuchel, N.; Singh, R.; Harvey, A.; Avery, T.; Chery, F.; Contreras, J. M.; Gay, J.; Michaut-Simon, C.; Morice, C.; Steffen, A. Assignee Company. Bionomics Limited Disease Area. Pain Biological Target. Nav1.7 Summary. The role of Nav1.7 in pain has recently gained significant attention as a result of genetic evidence linking this channel to pain disorders. Mutations in humans that increase Nav1.7 activity have been positively associated with two painful, inherited conditions, erythromelalgia and paroxysmal extreme pain syndrome. In contrast, loss of function mutations of this channel leads to congenital insensitivity to pain. These observations have sparked interest in Nav1.7 modulators as possible therapeutic agents for the treatment of pain. In addition, the wide distribution of Nav1.7 in the peripheral nervous system allows for the possibility of therapeutic intervention in pain without the need for central nervous system (CNS) penetration and the associated risk of CNSdriven adverse effects. The present application discloses compounds capable of blocking Na1.7 activity and their potential use as therapeutic agents for the treatment of pain. Definitions. R1 and R2 are independently selected from hydrogen, optionally substituted C1−6 alkyl, C1−6 haloalkyl, optionally substituted C3−C7 cycloalkyl, optionally substituted C5−C12 aryl, optionally substituted C2−C12 heterocyclyl; or R1 and R2, together with the N to which they are attached, form an optionally substituted C2−C12 heterocyclyl, or optionally substituted C2−C12 heteroaryl; R3 is selected from hydrogen, optionally substituted C1−C6 alkyl, optionally substituted C1−C6 haloalkyl, optionally substituted C1−C6 alkoxy, optionally substituted C3−C7 cycloalkyl, optionally substituted C3−C7 cycloalkenyl, optionally substituted acyl, optionally substituted C2−C12 heterocyclyl, or optionally substituted aryl; Y is a divalent linker group selected from C1−C5 alkylene, −(CH2)x−O−(CH2)y−, −(CH2)x−S(CH2)y−, wherein x and y are each integers independently selected from 0, 1, 2, and 3; © XXXX American Chemical Society
Biological Assay. Automated electrophysiological patch clamp (Patchliner, Nanion Technologies) of HEK293 cells expressing human Nav1.7. Biological Data.
Claims. 14 Total claims Received: July 27, 2019
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DOI: 10.1021/acsmedchemlett.9b00341 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
10 Composition of matter claims 4 Method of use claims Recent Review Articles. 1. McKerrall, S. J.; Sutherlin, D. P. Nav1.7 inhibitors for the treatment of chronic pain. Bioorganic & Medicinal Chemistry Letters 2018, 28 (19), 3141−3149. 2. Vetter, I.; Deuis, J. R.; Mueller, A.; Israel, M. R.; Starobova, H.; Zhang, A.; Rash, L. D.; Mobli, M. NaV1.7 as a pain target - From gene to pharmacology. Pharmacology & Therapeutics 2017, 172, 73−100. 3. Sun, S.; Cohen, C. J.; Dehnhardt, C. M. Inhibitors of voltage-gated sodium channel Nav1.7: patent applications since 2010. Pharmaceutical Patent Analyst 2014, 3 (5), 509−521. 4. Dib-Hajj, S. D.; Yang, Y.; Black, J. A.; Waxman, S. G. The NaV1.7 sodium channel: from molecule to man. Nat. Rev. Neurosci. 2013, 14 (1), 49−62.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Benjamin E. Blass: 0000-0003-2449-4503 Notes
The author declares no competing financial interest.
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DOI: 10.1021/acsmedchemlett.9b00341 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
