Axelopran

{{Short description|Chemical compound}}

{{Drugbox

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| IUPAC_name = 3-[(1R,5S)-8-[2-[cyclohexylmethyl-[(2S)-2,3-dihydroxypropanoyl]amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide

| image = Axelopran Structure.svg

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| CAS_number_Ref =

| CAS_number = 949904-48-7

| CAS_supplemental =
{{CAS|949904-50-1}} (sulfate)

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 85U7ROB149

| ATC_prefix = none

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| PubChem = 67156338

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| ChemSpiderID = 31444004

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D10740

| C=26 | H=39 | N=3 | O=4

| smiles = C1CCC(CC1)CN(CCN2C3CCC2CC(C3)C4=CC=CC(=C4)C(=O)N)C(=O)C(CO)O

| StdInChI =1S/C26H39N3O4/c27-25(32)20-8-4-7-19(13-20)21-14-22-9-10-23(15-21)29(22)12-11-28(26(33)24(31)17-30)16-18-5-2-1-3-6-18/h4,7-8,13,18,21-24,30-31H,1-3,5-6,9-12,14-17H2,(H2,27,32)/t21-,22+,23-,24-/m0/s1

| StdInChIKey = ATLYLVPZNWDJBW-KIHHCIJBSA-N

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}}

Axelopran (INN, USAN) (developmental code name TD-1211) is a drug which is under development by Theravance Biopharma and licensed to Glycyx for all indications. It acts as a peripherally acting μ-opioid receptor antagonist and also acts on κ-, and δ-opioid receptors, with similar affinity for the μ- and κ-opioid receptors and about an order of magnitude lower affinity for the δ-opioid receptor. Recent data suggests that μ-opioid antagonists have a direct effect on overall survival in patients with advanced cancer.{{cite journal | vauthors = Janku F, Johnson LK, Karp DD, Atkins JT, Singleton PA, Moss J | title = Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer | journal = Annals of Oncology | date = September 2016 | volume = 27 | issue = 11 | pages = 2032–2038 | doi = 10.1093/annonc/mdw317 | pmid = 27573565 | pmc = 6267944 }}

A μ-opioid agonist (e.g., morphine) have been shown to have multiple pro-tumor effects in vivo and in vitro, which can be blocked with μ-opioid antagonists including promoting angiogenesis,{{cite journal | vauthors = Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP | title = Morphine Stimulates Angiogenesis by Activating Proangiogenic and Survival-promoting Signaling and Promotes Breast Tumor Growth | journal = Cancer Research | volume = 62 | date = August 2002 | issue = 15 | pages = 4491–4498 | pmid = 12154060 }}{{cite journal | vauthors = Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J | title = Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: Role of receptor transactivation | journal = Microvascular Research | volume = 72 | date = September 2006 | issue = 1–2 | pages = 3–11 | doi = 10.1016/j.mvr.2006.04.004 | pmid = 16820176 }} accelerating tumor cell proliferation,{{cite journal | vauthors = Fujioka N, Nguyen J, Chen C, Li Y, Pasrija T, Niehans G, Johnson KN, Gupta V, Kratzke RA, Gupta K | display-authors = 7 | title = Morphine-induced epidermal growth factor pathway activation in non-small cell lung cancer | journal = Anesthesia and Analgesia | date = October 2014 | volume = 113 | issue = 6 | pages = 1353–1364 | doi = 10.1213/ANE.0b013e318232b35a | pmid = 22003224 | pmc = 3725599 }}{{cite journal | vauthors = Lennon FE, Mirzapoiazova T, Mambetsariev B, Poroyko VA, Salgia R, Moss J, Singleton PA | title = The Mu Opioid Receptor Promotes Opioid and Growth Factor-Induced Proliferation, Migration and Epithelial Mesenchymal Transition (EMT) in Human Lung Cancer | journal = PLOS ONE | volume = 9| date = March 2014 | issue = 3 | pages = e91577 | doi = 10.1371/journal.pone.0091577 | pmid = 24662916 | pmc = 3963855 | bibcode = 2014PLoSO...991577L | doi-access = free }} and modifying the response to chemotherapeutics. An extensive body of literature has shown diverse and profound immunosuppressive effects of μ-opioid activation in vivo and in vitro.{{cite journal | vauthors = Eisenstein TK | title = The Role of Opioid Receptors in Immune System Function | journal = Frontiers in Immunology | date = 2019 | volume = 10 | page = 2904 | doi = 10.3389/fimmu.2019.02904 | pmid = 31921165 | pmc = 6934131 | doi-access = free }}

Recent data for axelopran in three different pre-clinical models of cancer shows that a μ-opioid antagonist isolates distinct effects of the endogenous opioid system on tumor growth and works in combination with checkpoint inhibitors. The study of axelopran in melanoma in a zebrafish embryo model with an immature immune system and no microbiome tested axelopran direct effects on tumor growth and metastasis. The study of breast cancer in chicken eggs with a functional immune system and no microbiome tested the direct effect of axelopran on tumor weight, tumor immune infiltration, metastasis and angiogenesis. The study of axelopran in MC-38 syngeneic colorectal cancer in mice in combination with murine anti-PD-1 antibody tested the effect of a μ-opioid blockade on tumor volume and survival in a full in vivo model with both fully functional immune system and mature gut function and enteric microbiome.

All three pre-clinical studies showed a significant impact of axelopran on their respective endpoints, suggesting that μ-opioid blockade is useful across different tumor types and has multiple mechanisms of action, including direct suppression of tumor cell proliferation, angiogenesis and metastasis, and immune surveillance. Furthermore, axelopran and murine anti-PD-1 antibody were synergistic in slowing tumor growth and increasing survival in the syngeneic mouse model.

Axelopran has potent μ-opioid receptor antagonist activity on the gastrointestinal tract in vivo, and thus it produces a dose-dependent inhibition of opioid-induced delaying in gastric emptying in mice and rats following subcutaneous or oral administration.{{cite journal | vauthors = Armstrong SR, Campbell CB, Richardson CL, Vickery RG, Tsuruda PR, Long DD, Hegde SS, Beattie DT | display-authors = 6 | title = The in vivo pharmacodynamics of the novel opioid receptor antagonist, TD-1211, in models of opioid-induced gastrointestinal and CNS activity | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 386 | issue = 6 | pages = 471–8 | date = June 2013 | pmid = 23512167 | doi = 10.1007/s00210-013-0844-5 | s2cid = 15482326 }}{{cite journal | vauthors = Tsuruda PR, Vickery RG, Long DD, Armstrong SR, Beattie DT | title = The in vitro pharmacological profile of TD-1211, a neutral opioid receptor antagonist | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 386 | issue = 6 | pages = 479–91 | date = June 2013 | pmid = 23549670 | doi = 10.1007/s00210-013-0850-7 | s2cid = 18963203 }}