Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Acyl Sulfonamides NaV1.7 Blockers Useful for the Treatment of Pain Benjamin E. Blass* Temple University School of Pharmacy, Moulder Center for Drug Discovery Research, Philadelphia, Pennsylvania 19140, United States R2 is hydrogen or halo; R3 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and is substituted with 0−3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, (cycloalkyl)alkoxy, haloalkoxy, and NHCO2R8; R4 is hydrogen or alkyl; R5 is hydrogen or alkyl; R6 is hydrogen or alkyl; R7 is hydrogen or alkyl; or NR 6 R 7 taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0−3 halo or alkyl substituents; R8 is alkyl; and Ar1 is phenyl or thienyl and is substituted with 0−3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Key Structures.
Important Compound Classes.
Title. Acyl sulfonamide NaV1.7 inhibitors Patent Application Number. WO 2017/184658 A1 Publication Date. October 26th, 2017 Priority Application. US62/625,375 Priority Date. April 20th, 2016 Inventors. Luo, G.; Chen, L. Assignee Company. Bristol-Myer Squibb Company Disease Area. Pain Biological Target. NaV1.7 Summary. Voltage gated sodium channels (NaV) are key proteins that control the flow of sodium ions across membranes in the majority of excitable cells. Their structural features can be divided into two distinct subunits. The alpha subunit is a single large protein that contains four functional domains that controls gating and conduction. Each of these domains contains six transmembrane segment (S1−S6), four of which comprise the voltage sensing domain (S1−S4) and two that comprise the pore forming region (S5−S6). The beta subunit, however, has a single transmembrane segment and a large extracellular immunoglobin-like region. This portion of the NaV channel plays a role in controlling expression, gating, localization of the alpha subunit, and interacts with the extracellular matrix and intracellular cytoskeleton. To date, nine mammalian NaV genes have been identified, and they are referred to as NaV1.1 through NaV1.9. NaV1.7 is primarily expressed in peripheral sensory neurons and has been linked to pain sensation. Specifically, it has been demonstrated that loss of function mutations in the NaV1.7 gene (SCN9A) leads to congenital insensitivity to pain (CIP) in humans. Patients with this condition do not sense pain, even with significant injuries. Similarly, NaV 1.7 knockout mice do not respond to mechanical, inflammatory, and neuropathic pain stimuli. Gain of function of the NaV1.7 gene, however, has been linked to the inherited pain syndromes inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN). These finding suggest that blockade of NaV1.7 may have therapeutic value in the treatment of pain. The current disclosure describes a series of acyl sulfonamides capable of blocking NaV1.7 and their method of use for the treatment of pain. Definitions. X is CH and Y is NR4; or X is NR5 and Y is N; R1 is alkyl, haloalkyl, cycoalkyl, NR6R7 or Ar1; © XXXX American Chemical Society
Biological Assay. The following assays were employed to identify compounds of interest: Ion Works Barracuda population patch clamp using NaV1.7 expressing HEK 293 cells. Received: January 22, 2018
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DOI: 10.1021/acsmedchemlett.8b00038 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
NaV1.7 ligand binding assay (LBA) using purified membranes from NaV1.7 expressing HEK 293 cells. Ion Works Barracuda population patch clamp using NaV1.5 expressing HEK 293 cells. Biological Data.
Claims. 9 Total claims 8 Composition of matter claims. 1 Method of use claims. Recent Review Articles. 1. 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 and Therapeutics 2017, 172, 73−100. 2. Emery, E. C.; Luiz, A. P.; Wood, J. N. Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert Opinion on Therapeutic Targets 2016, 20 (8), 975−983. 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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AUTHOR INFORMATION
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[email protected]. Notes
The author declares no competing financial interest.
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DOI: 10.1021/acsmedchemlett.8b00038 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
