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EP-4734977-A2 - NOVEL TRPV1 AGONISTS AND USES THEREOF

EP4734977A2EP 4734977 A2EP4734977 A2EP 4734977A2EP-4734977-A2

Abstract

Novel TRPV1 agonists and uses thereof are provided, including modified resiniferatoxin (RTX) to desensitize TRPV1 -expressing neurons. The modified RTX disclosed herein may comprise at least one substitution on the distal 6-membered ring of RTX, a replacement of the 6-membered distal ring of RTX, or at least one alteration of resiniferonol 9, 13, 14-ortho-phenylacetate, which can further comprise at least one substitution on the distal 6-membered ring of RTX and/or a replacement of the 6-membered distal ring of RTX

Inventors

  • TAVARES, FRANCIS, X.

Assignees

  • Neucures, Inc.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. A compound comprising a modified RTX.
  2. 2. The compound of claim 1, wherein the modified RTX comprises at least one substitution on the distal 6-membered ring of RTX.
  3. 3. The compound of claim 1, wherein the modified RTX comprises a replacement of the 6- membered distal ring of RTX.
  4. 4. The compound of claim 1, wherein the modified RTX comprises at least one alteration of resiniferonol 9, 13,14-ortho-phenylacetate.
  5. 5. The compound of claim 4, wherein the modified RTX further comprises at least one substitution on the distal 6-membered ring of RTX.
  6. 6. The compound of claim 4, wherein the modified RTX further comprises a replacement of the 6-membered distal ring of RTX.
  7. 7. A compound comprising:
  8. 8. A compound comprising:
  9. 9. A compound comprising:
  10. 10. A compound comprising:
  11. 11. The compound of claim 10, wherein X comprises CH2.
  12. 12. The compound of claim 10, wherein n comprises 1-3.
  13. 13. The compound of claim 10, wherein R1 is selected from the group consisting of H, Me, haloalkyl, cycloalkyl, and alkyl and R2 comprises H.
  14. 14. The compound of claim 10, wherein R2 is selected from the group consisting of H, Me, haloalkyl, cycloalkyl, and alkyl and R1 comprises H.
  15. 15. A compound comprising:
  16. 16. The compound of claim 15, wherein X comprises CH2.
  17. 17. The compound of claim 15, wherein m comprises 2-3.
  18. 18. The compound of claim 15, wherein Y comprises CH2.
  19. 19. The compound of claim 15, wherein comprises 1-3.
  20. 20. A compound comprising:

Description

NOVEL TRPV1 AGONISTS AND USES THEREOF BACKGROUND [001] Transient receptor potential vanilloid (TRPV) channels are a family of nonselective cation channels that are present on the cell membranes of various cells throughout the body. Of this family, transient receptor potential vanilloid subtype 1 (TRPV1) channels located on sensory neurons and are responsible for the transduction of noxious stimuli such as heat and pain. Exogenous agonists of TRPV1 such as capsaicin and resiniferatoxin (RTX) depolarize TRPV1- expressing neurons and can be specifically used to desensitize this population of neurons. Thus, the use of exogenous TRPV1 agonists is emerging as a method to provide analgesia (e.g., inflammatory pain, neuropathic pain, cancer pain) as well as to treat a range of clinical conditions such as cardiovascular diseases (e.g., heart failure, arrhythmias), overactive bladder, gastrointestinal disease (e.g., irritable bowel syndrome), cough, and asthma. [002] Accordingly, there is a need for novel TRPV1 agonists that can desensitize neurons. SUMMARY [003] The present disclosure is directed to a family of compounds comprising a modified RTX. In an embodiment, the modified RTX comprises at least one substitution on the distal 6-membered ring of RTX. In another embodiment, the modified RTX comprises a replacement of the 6- membered distal ring of RTX. In another embodiment, the modified RTX comprises at least one alteration of resiniferonol 9,13,14-ortho-phenylacetate, which can further comprise at least one substitution on the distal 6-membered ring of RTX and/or a replacement of the 6-membered distal ring of RTX. [004] The present disclosure is also directed to a compound comprising certain chemical structures disclosed herein and/or a composition comprising the chemical structures disclosed herein and further comprising an excipient. In an embodiment, the excipient is selected from at least one of the group consisting of ethanol, methanol, polyethylene glycol, dimethyl sulfoxide, sodium chloride, or a cyclodextran. In another embodiment, the composition further comprises a solubility enhancer. In an embodiment, the solubility enhancer comprises a protein, including but not limited to albumin or a derivative thereof. [0051 The present disclosure is also directed to a method of administering the compounds or compositions disclosed herein to a subject in need thereof. In an embodiment, the method comprises administration by at least one of topical, subcutaneous, epicardial, epidural, intrathecal, peri or intra-ganglionic, vascular, intraarticular, interarticular, pericardial, intrapericardial, or intravesical administration. DRAWINGS [006] FIG. 1 depicts the synthesis schematic of COMPOUND 3. [007] FIG. 2 depicts the synthesis schematic of COMPOUND 5. [008] FIG. 3 depicts the synthesis schematic of COMPOUND 7. [009] FIG. 4 depicts the synthesis schematic of COMPOUND 9. [0010] FIG. 5 depicts the synthesis schematic of COMPOUND 11. [0011] FIG. 6 depicts the synthesis schematic of COMPOUND 13. [0012] FIG. 7 depicts the synthesis schematic of COMPOUND 15. [0013] FIG. 8 depicts the synthesis schematic of COMPOUND 17. [0014] FIG. 9 depicts the synthesis schematic of COMPOUND 19. [0015] FIG. 10 depicts the synthesis schematic of COMPOUND 21. [0016] FIG. 11 depicts the synthesis schematic of COMPOUND 23. [0017] FIG. 12 depicts the TRPV1 agonist assay data for COMPOUNDS 3, 5, 7, 9, and 11, RTX, and Capsaicin. [0018] FIG. 13A depicts the TRPV1 agonist assay data for COMPOUNDS 13, 15, 17, 19, and 21. [0019] FIG. 13B depicts the TRPV1 agonist assay data for COMPOUNDS 23, 9, and 11, RTX, and Capsaicin. [0020] FIG. 14 depicts the estimated EC50 (nM) of COMPOUNDS 13, 15, 17, 19, 21, 23, 9, and 11, and RTX. [0021] FIG. 15 depicts the TRPV1 agonist assay data for RTX and capsaicin. [0022] FIG. 16 depicts desensitization studies of COMPOUNDS 13 and 21, RTX, and Capsaicin. [0023] FIG. 17A presents the data for a TRPV1 agonist assay performed on COMPOUND 21. [0024] FIG. 17B presents the data for a TRPV1 agonist assay performed on RTX, capsaicin, and capsazepine. [0025] FIG. 18A graphically depicts the data from the TRPV1 agonist assay performed on COMPOUND 21. [0026] FIG. 18B graphically depicts the data from the TRPV1 agonist assay performed on RTX. [0027] FIG. 18C graphically depicts the data from the TRPV1 agonist assay performed on capsaicin. [0028] FIG. 18D graphically depicts the data from the TRPV1 agonist assay performed on capsazepine. [0029] FIG. 19 depicts a study protocol for evaluation of COMPOUND 21 and COMPOUND 9 in a pig model. [0030] FIG. 20A depicts the heart rate change during the study protocol depicted in FIG. 19 for COMPOUND 21. [0031] FIG. 20B depicts the blood pressure change during the study protocol depicted in FIG. 19 for COMPOUND 21. [0032] FIG. 20C depicts the heart rate change during the study protocol depicted in FIG. 19 for COMPOUND 9. [0033] FIG. 20D depicts the blood pressure change during the