Fused Heterocyclic Compounds as Ion Channel Modulators: Patent Highlight

Benjamin Blass

doi:10.1021/ml300158j

editorial

. 2012 Jul 2;3(8):616–617. doi: 10.1021/ml300158j

Fused Heterocyclic Compounds as Ion Channel Modulators

Patent Highlight

Benjamin Blass ^1,^*

PMCID: PMC4025751 PMID: 24900521

Title:	Fused Heterocyclic Compounds as Ion Channel Modulators
Patent/Patent Application Number:	WO2012003392A1	Publication Date:	January 5, 2012
Priority Application:	US61/361056	Priority Date:	July 2, 2010
Inventors:	Kobayashi, Tetsuya; Koltun, Dmitry; Notte, Gregory; Parkhill, Eric; Zablocki, Jeff
Assignee Company:	Gilead Science Inc.
Disease Area:	Cardiovascular Disease	Biological Target:	Voltage Gated Sodium Channel Na_v1.5
Summary:	Voltage-gated sodium channels play an important role in both cardiac myocytes and neuronal cells. The Na_v1.5 channel is responsible for the late sodium current (INaL), and dysfunction of this channel can contribute to the development of a variety of disease states associated with abnormally high Na_v1.5 activity. Ranexa, a selective INaL inhibitor, has clinical utility for the treatment of stable angina pectoris, unstable angina, and arrhythmia. This patent application discloses a series of functionalized triazolopyridin-3-ones that are useful as Na_v1.5 channel inhibitors for the treatment cardiovascular diseases associated with increased Na_v1.5 activity.
Important Compound Classes:
Definitions:	R¹ is aryl, heteroaryl.
	R² is hydrogen, C_1–15 alkyl, C_1–8 alkoxy, −C(O)OR²⁶, −C(O)N(R²⁶)(R²⁸), N(R²⁰)SO₂R²⁰, cycloalkyl, aryl, heteroaryl, heterocyclyl.
	R³ is hydrogen, OH, halogen, C_1–4 alkyl, C_1–4 alkoxy, −R²⁵–N(R²⁰)(R²²), −R²⁵–OR²⁰, −R²⁵C(O)OR²⁰, −R²⁵C(O)N(R²⁰)(R²²), −R²⁵C(O)ON(R²⁰)(R²²), −R²⁵N(R²⁰)C(O)R²², −R²⁵OC(O)N(R²⁰)(R²²).
	R⁴ is hydrogen, C_1–4 alkyl, aryl, CF₃, halo, −OR²⁴.
	R⁵ is hydrogen, optionally substituted alkyl, amino, optionally substituted alkoxy, CF₃, OCF₃, CN, −N(R²⁰)C(O)R²².
Key Structures:
Recent Review Articles:	Rook M. B.; Evers M. M.; Vos M. A.; Bierhuizen M. F. A.. Biology of cardiac sodium channel Na_v1.5 expression. Cardiovasc. Res. 2012, 93 (1), 12–23.
Biological Assay:	Whole cell electrophysiological patch clamp (PatchXpress7000A MDS Analytical Technologies) using HEK293 cells expressing hNa_v1.5. Inhibition of hNa_v1.5 is reported as a percent inhibition at 1.0 μM.
Biological Data:	Table 1: Exemplary hNa_v1.5 Inhibition Data

Synthesis:
Claims:	The application claims the compounds of the disclosure and their use for the treatment of cardiovascular disease, diabetes, diabetic peripheral neuropathy, neuropathic pain, epilepsy, seizures, and paralysis.
Additional Information:	The application provides methods for screening of compounds against the following additional ion channels: L-type calcium, Na_v1.7, Na_v1.1, and Na_v1.2.