Patent Highlight pubs.acs.org/acsmedchemlett
Sodium Channel Blockers Benjamin Blass* Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, United States Title:
Sodium channel blockers
Patent Application Number:
WO2016129933
Publication date:
August 18, 2016
Priority Application:
KR10−2015−0021160
Priority date:
February 11, 2015
Assignee Company:
Daewoong Pharmaceutical Co.
Disease Area:
Pain
Biological Target:
Nav1.7
Summary:
Maintaining a specific membrane potential is a critical to various cellular functions in a variety of mammalian cells. The heart, central and peripheral nervous system, and muscle function all depend on the proper regulation and timing of changes in membrane potential. Voltage gated sodium channels play a key role in these processes. To date, nine voltage gated sodium channels, designated Nav1.1 to Nav1.9 have been identified, and improper activity can lead to a number of negative health consequences. Nav1.7, for example, has been linked to the sensation of pain. Loss of function mutations of this ion channel have been document in humans and lead to congenital insensitivity to normally painful stimuli. Increased Nav1.7, however, has been associated with increased sensitivity to pain. These observations suggest that Nav1.7 blockade may be a viable method of treating chronic pain, and compounds such as Raxatrigine (CNV1014802), a Nav1.7 blocker that recently completed phase II clinical trials for the treatment of lumbar radiculopathy (sciatica), appear to have validated this hypothesis. The present disclosure describes a series of compounds capable of modulating Nav1.7 activity and their use as treatment for pain and pain related disorders such as acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathy, nerve injury, visceral pain, paroxysmal extreme pain disorder (PEPD), erythromelalgia, and diabetic neuropathy. The current disclosure also claims the use of the compounds described therein for the preventing or treating sodium channel blocker diseases such as epilepsy, arrhythmia, myotonia, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, and depression.
Important Compound Classes:
Definitions:
X1 is C-Ra or N, X2 is C-Rb or N, X3 is C-Rc or N, X4 is C-Rd or N; Ra, Rb, Rc, and Rd are each independently hydrogen, C1−4alkyl, C3−6cycloalkyl, Cl‑4 alkoxy, C6−10aryl, 5-membered or 6-membered heteroaryl, halogen or cyano; X5 is CR, N, or OH, X6 is C-Re or N, X7 is CH or N, X8 is C-Rf or N; Re is hydrogen; C1−4alkyl; C2−4alkynyl, which is unsubstituted or substituted with C1−4hydorxyalkyl; C3−6cycloalkyl; −COO-(C1−4alkyl); -NHCO-(C1−4alkyl); −CHCH− (pyridinyl); amino; carboxy; cyano; halogen; morpholino; 5-membered or 6-membered heteroaryl, which is unsubstituted or substituted with a substituent selected from the group consisting of C1−4alkyl, C1−4alkoxy, amino, and halogen; phenyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1−4alkyl, C1−4alkoxy, C1−4haloalkyl, C1−4haloalkoxy, halogen, amino, cyano, and nitro; pyridin-2-onyl, which is unsubstituted or substituted with C1−4alkyl; styryl, which is unsubstitued or substituted with a substituent selected from the group consisting of C1−4halolkyl and halogen; or tetrahydropyridinyl, which is unsubstituted or substituted with −COO-(C1−4alkyl); Rf is halogen, benzyloxy, or phenyl; X9 is C-Rg or N; Rg is hydrogen; C1−4alkyl; C1−4alkoxy, which is unsubstituted or substituted with a substituent selected from the group consisting of C3−6cycloalkyl, phenyl, phenyl substituted with halogen, and naphthyl; C1−4haloalkyl; C3−6cycloalkyl; amino; halogen; hydroxy; nitro; phenylamino; benzyloxy, which is unsubstituted or substituted with halogen; phenyl, which is unsubstituted or substituted with one to three substituents independently selected from the group consisting of C1−4alkyl, C1−4alkoxy, C1−4haloalkyl, cyano, amino, nitro, and halogen; 5-membered or 6-membered heteroaryl, which is unsubstituted or substituted with a substituent independently selected from the group consisting of C1−4alkyl and halogen; or pyridinyloxy, which is unsubstituted or substituted with halogen; X10 is C-Rh or N; Rh is hydrogen, halogen, or benzyloxy; R is −CO-N(Ri)-SO2-Rii, −SO2−NH-Riii, −CONH-Riv, cyano, dihydrotriazolonyl, or tetrazolyl; Ri is hydrogen; C1−4alkyl; naphthylmethyl; or benzyl, which is unsubstituted or substituted with halogen; Rii is C1−4alkyl or N (C1−4alkyl)2; Riii is 5-membered or 6-membered heteroaryl, which is unsubstituted or substituted with a substituent selected from the group consisting of C1−4alkyl and halogen; and Riv is hydrogen; −CO-(C1−4alkyl); -NHCO-NH2; or thiazolyl, which is unsubstituted or substituted with a substituent selected from the group consisting of C1−4alkyl and −COO-(C1−4alkyl).
Received: February 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00048 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Key Structures:
Recent Review Rivara, M.; Zuliani, V. Novel sodium channel antagonists in the treatment of neuropathic pain. Expert Opin. Invest. Drugs 2016, 25 (2), 215−226. Articles: Sun, S.; Cohen, C. J.; Dehnhardt, C. M. Inhibitors of voltage-gated sodium channel Nav1.7: patent applications since 2010. Pharm. Patent Analyst 2014, 3 (5), 509−521. King, G. F.; Vetter, I. No Gain, No Pain: NaV1.7 as an Analgesic Target. ACS Chem. Neurosci. 2014, 5 (9), 749−751. Biological Nav1.7 automated patch clamp: Assay: An IonFlux16 auto patch clamp system (Fluxion, Inc.) was employed to determine biological activity of test compounds. HEK293 cells stably expressing hNav1.7 distributed in an extracellular solution (4 mM KCl, 138 mM NaCl, 1 mM MgCl2, 1.8 mM CaCl2, 5.6 mM glucose, 10 mM HEPES, pH 7.45) and then dispensed in the specified region of a microtiter plate. Test compounds were diluted at various concentrations and then dispensed in specified region of the microtiter plate. After the dispensation of the cells, the test compounds, and an intracellular solution (100 mM CsF, 45 mM CsCI, 5 mM NaCl, 5 mM EGTA, 10 mM HEPES, pH 7.2) in the plate has been completed, the plate was attached to the patch clamp system, and whether the test compounds inhibited the ion channel was determined according to a setting program and pulse protocol. Specifically, eight concentrations per test compound were set, and percent inhibition was determined by calculating the percentage of inhibition of the peak current, generated after treating the cells with each concentration of the test compound for 50 s, relative to the peak current generated before treatment with the test compound, and the IC50 value was calculated using Sigma Plot program. Biological Data:
Claims:
20 Total claims 19 Composition of matter claims 1 Method of use claim
B
DOI: 10.1021/acsmedchemlett.7b00048 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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Patent Highlight
AUTHOR INFORMATION
Corresponding Author
*Tel: 215-707-1085. E-mail:
[email protected]. Notes
The author declares no competing financial interest.
C
DOI: 10.1021/acsmedchemlett.7b00048 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
