Important Compound Classes
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 CNS-driven 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;
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
Biological Assay
Automated electrophysiological patch clamp (Patchliner, Nanion Technologies) of HEK293 cells expressing human Nav1.7.
Biological Data
Claims
14 Total claims
10 Composition of matter claims
4 Method of use claims
Recent Review Articles
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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.
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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.
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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.
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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.
The author declares no competing financial interest.