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„ Wo 2012/012498 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau „ (10) International Publication Number (43) International Publication Date . _ 26 January 2012 (26.01.2012) WO 2012/012498 A2 (51) International Patent Classification: (71) Applicant (for all designated States except US): PUL- A61K 45/06 (2006.01) A61K 31/496 (2006.01) MATRIX, INC. [US/US]; 99 Hayden Avenue, Lexing A61K 31/23 (2006.01) A61P 31/04 (2006.01) ton, Massachusetts 02421 (US). A61K 31/235 (2006.01) A61P 31/12 (2006.01) A61K 31/381 (2006.01) (72) Inventors; and (75) Inventors/Applicants (for US only): HAVA, David L. (21) International Application Number: [US/US]; 68 S. Main Street, #2, Natick, Massachusetts PCT/US201 1/044628 01760 (US). CLARKE, Robert W. [US/US]; 10 Knoll- wood Road, Medfield, Massachusetts 02052 (US). (22) International Filing Date: 20 July 201 1 (20.07.201 1) (74) Agents: UNDERWOOD, Robert H. et al; Mcdermott Will & Emery LLP, 28 State Street, Boston, Mas (25) Filing Language: English sachusetts 02 109 (US). English (26) Publication Language: (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 61/365,840 20 July 2010 (20.07.2010) US AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, [Continued on nextpage] (54) Title: USE OF TRP CHANNEL AGONISTS TO TREAT INFECTIONS (57) Abstract: Methods are described for treating or preventing a respira- A. Ruthenium red tory infection by administering an effective amount of a TRP channel ag- i r R 8X 8X RR B. SKF96365 r SKF SX 8X SKF w o 2012/012498 A2 1II 11 II II III III I III II I Hill I III i ll CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, GW, ML, MR, NE, SN, TD, TG). KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, Declarations under Rule 4.17: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, — as to applicant's entitlement to apply for and be granted SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, a patent (Rule 4.1 7(H)) TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. — as to the applicant's entitlement to claim the priority of (84) Designated States (unless otherwise indicated, for every the earlier application (Rule 4. 17( i)) Mnd of regional protection available): ARIPO (BW, GH, Published: GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, — without international search report and to be republished TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, upon receipt of that report (Rule 48.2(g)) EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, USE OF TRP CHANNEL AGONISTS TO TREAT INFECTIONS RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 61/365,840, filed on July 20, 2010. The entire contents of the foregoing application is hereby incorporated by reference. RELATED APPLICATIONS [0002] Transient receptor potential (TRP) channels represent a large superfamily of homologous membrane proteins. TRP channels are expressed throughout the body, and several TRP channel family members can be expressed on a single cell type. TRP channels are composed of six-transmembrane (6TM) polypeptide subunits that combine to form tetramers. These tetramers form pores in the membrane that are permeable to cations (e.g., Ca + and Na+). TRP channel activation allows for rapid, yet controlled, entry of one or more cations into a cell, and are involved in sensory transduction in response to a diverse array of physiological stimuli. (Clapham D E. TRP channels as cellular sensors. Nature. 2003. 426:517-524.) TRP channels are classified into subfamilies based on sequence homology, which include the TRPC, TRPV, TRPM and TRPA1 subfamilies. [0003] TRPC (where "C" represents "classic" or "canonical") channel subfamily members are G-protein-coupled receptor (GPCR) or receptor tyrosine kinase activated channels. TRPC1, TRPC4 (CCE2), and TRPC5 (CCE1) are highly homologous, are expressed in the central nervous system (CNS) and form homo or heteromeric channels. (Clapham 2003) TRPC3, TRPC6, and TRPC7 are also highly expressed in smooth and cardiac muscle cells and may be involved in the regulation of vascular tone, airway resistance, and/or cardiac function. (See Clapham 2003; Trebak M, Vazquez G, Bird G S, Putney, J W. The TRPC3/6/7 subfamily of cation channels. Cell Calcium. 2003. 33(5-6):451- 461.) [0004] The TRPV (where "V" represents "vanilloid") channel subfamily members are more selective for Ca + than other TRP subfamilies, and TRPV5 and TRPV6 are the most Ca + selective TRP channels. (Clapham 2003) TRPVl (VR1), TRPV2 (VRL1, OTRPC2), TRPV3 (VRL2) and TRPV4 (OTRPC4, VR-OAC) are activated by elevated temperatures. These four TRPV channels are also thought to be activated by cell stretching that is likely due to detecting changes in extracellular tonicity, and specifically hypotonicity. (Birder L A, et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPVl. Nat Neurosci. 2002. 5(9):856-860; Iwata Y, et al. A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel. J Cell Biol. 2003. 161(5):957-967; Hu H Z, et al. 2-aminoethoxydiphenyl borate is a common activator of TRPVl, TRPV2, and TRPV3. J Biol Chem. 2004. 279(34):35741-35748.) TRPV5 (ECaCl, CaT2) and TRPV6 (ECaC2, CaTl) are the only TRPV channels not known to possess thermosensory activity. Both TRPV5 and TRPV6 are expressed in the intestines, are constitutively active, and are inhibited by intracellular Ca + concentrations, which suggests a role in calcium absorption. (Clapham D E. SnapShot: Mammalian TRP Channels. Cell. 2007. 129(1):220; den Dekker E, et al. The epithelial calcium channels, TRPV5 & TRPV6: from identification towards regulation. Cell Calcium. 2003. 33(5-6):497-507; Hoenderop J G, et al. Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J. 2003. 22(4):776-785.) [0005] The TRPM (where "M" represents "melastatin") channel subfamily takes its name from the observed over-expression of TRPMl (MLSN) transcripts in certain metastatic melanomas. TRPM2 (hTRPC7, LTRPC2) is gated by binding of ADP-ribose and NAD (nicotinic adenine dinucleotide) to its C-terminal hydrolase domain. TRPM3 (MLSN2, LTRPC3), like TRPV4, is sensitive to hypotonicity, but there is little homology to suggest a common mechanism of action. TRPM4 (LTRPC4, MLS2s, CAN[4b]) and TRPM5 (Mtrl, LTRPC5) are the only TRP channels that are monovalent cation-selective. TRPM4 is widely expressed, and TRPM4 deficient mice have enhanced anaphylactic responses. (Clapham 2003; Clapham 2007) TRPM5 is also widely expressed, and plays a role in the taste perception of sweet, bitter and umami (amino acid) sensations. (Zhang Y, et al. Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell. 2003. 112(3):293-301.) TRPM6 (CHAK2) and TRPM7 (CHAK, TRP-PLIK, LTRPC7) contain a functional kinase domain, but this domain is not necessary for the channel activity. (Runnels L W, et al. The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nat Cell Biol. 2002. 4(5):329-336.; Schmitz C, et al. Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell. 2003. 114(2): 191-200.) TRPM7 is thought to play a role in monitoring intracellular energy stores by sensing Mg-ATP levels. (Nadler M J, et al. LTRPC7 is a Mg- ATP regulated divalent cation channel required for cell viability. Nature. 2001 . 4 11:590-595.) TRPM8 (Trp-p8, CMRl) is involved in detecting "cooling" and noxious cold sensations from ~8 °C to 28 °C. Menthol and icilin are agonists that enhance the sensory transduction of TRPM8. (Clapham 2003; McKemy D D, et al. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002. 416:52-58; Peier A M, et al. A TRP channel that senses cold stimuli and menthol. Cell. 2002. 108(5):705-715.) [0006] TRPA1 (ANKTM1, P120), (where "A" represents "ankyrin") is the only member of the TRPA subfamily. TRPA1 is activated by temperatures below 15 °C. Although there is no significant homology to TRPM8, TRPA1 is activated by the TRPM8 agonist icilin. (Clapham 2007; Story G M, et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003. 112(6):819-829.) TRPA1 is usually co-expressed in TRPV1 positive dorsal root ganglion neurons that do not express TRPM8. (Clapham 2003; Kobayashi K, et al. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. J Comp Neurol. 2005. 493(4):596-606.) [0007] Some TRP channel agonists, such as the vanilloid capsaicin, are known pain relievers. (Tominaga M, Julius D. Capsaicin receptor in the pain pathway. Jpn J Pharmacol. 2000. 83(l):20-24; Cortright D N, Szallasi A. TRP channels and pain. Curr Pharm Des. 2009. 15(15):1736-1749.) [0008] Certain TRPV3 agonists may be useful for treating inflammatory-associated conditions, including asthma and inflammatory bowel disorder (See, e.g., WIPO Patent Publication WO2008065666) or allergic and non-allergic rhinitis (See US Patent Publication No.
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