N-(2-Alkyleneimino-3-phenylpropyl)acetamide Compounds and Their Use against Pain and Pruritus via Inhibition of TRPA1 Channels

Title:	N-(2-Alkyleneimino-3-phenylpropyl)acetamide compounds and their use against pain and pruritus via inhibition of TRPA1 channels
Patent Application Number:	WO2016067143	Publication date:	May 6th, 2016
Priority Application:	US62,069,457	Priority date:	October 28th, 2014
Inventors:	Swain, N. A.; Pryde, D. C.; Rawson, D. J.; Ryckmans, T.; Skerratt, S. E.; Amato, G. S.; Marron, B. E.; Reister, S. M.; West, C. W.
Assignee Company:	Pfizer, Inc.
Disease Area:	Pain and pruritus	Biological Target:	TRPA1 Channel
Summary:	The transient receptor potential (TRP) channel superfamily consists of a series of cation channels that are critical to a wide range of physiological processes. Members of this class of ion channels are responsible for defensive reactions to environmental stressors such as coughing, pain, and alterations in respiratory patterns. A significant amount of research has been devoted to the identification of modulators of TRP channels in an effort to develop novel therapeutics. The TRPA1 channel is of particular interest, as it is sensitive to cold, abnormal pH, and reactive irritants. Site directed mutagenesis experiments have identified three cysteine residues (Cys621, Cys641, and Cys665) in human TRPA1 that are critical to its function under certain conditions. When all three are replaced, TRPA1 no longer responds to a variety of electrophilic reagents, but the reason for this alteration in response profile remains a mystery. The present application discloses a series of novel compounds capable of inhibiting the TRPA1 channel that are potential therapies for the treatment of pain and pruritus.
Important Compound Classes:
Definitions:	RA and RB are each independently (C1–C3)alkyl, or RA and RB together are −(CH2)a– or −(CH2)2O(CH2)2–;
	RC is selected from (C1–C3)alkyl, (C1–C3)polyfluoroalkyl, and;
	R1 R2, R3, R4, R5, and R6 are each independently selected from H, halo, OH, CH3, CF3, OCH3, and CN;
	X is H or OH;
	Y is C(H) or N;
	a is 2, 3, 4, or 5; and
	n is 1 or 2.
Key Structures:
Recent Review Articles:	Tominaga M.Temperature-Sensitive TRP Channel and Diseases. Farumashia 2015, 51 ( (11), ), 1047–1052.
	Nassini R.; Materazzi S.; Benemei S.; Geppetti P.. The TRPA1 Channel in Inflammatory and Neuropathic Pain and Migraine. Reviews of Physiology, Biochemistry and Pharmacology 2014, 167, 1–43.
	Preti D.; Saponaro G.; Szallasi A.. Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists. Pharmaceutical Patent Analyst 2015, 4 ( (2), ), 75–94.
Biological Assay:	Electrophysiological assays were conducted with PatchXpress 7000 hardware and associated software (Molecular Devices, Sunnyvale, CA) or on a manual patch clamp station using a stable clonal hTRPA1/293-T-REx cell line. The aforementioned cell line was designed to allow induction of hTRPA1 expression via exposure to tetracycline.
Biological Data:
Claims:	21 total claims.
	10 composition of matter claims.
	11 method of use claims.

The authors declare no competing financial interest.