Levamisole derivatives as immune modulators for the treatment of amyotrophic lateral sclerosis (ALS).

Aim: To discover derivatives of the anthelmintic drug levamisole, which has been reported to possess immune-modulatory properties, as treatments for amyotrophic lateral sclerosis (ALS), which has been suggested to be in part an autoimmune disease. Results: We have synthesized ten analogs of the racemic version of levamisole, tetramisole, as well as eleven analogs on a related system. All of the analogs have been tested for their ability to affect the response of five ALS-relevant cytokines. Conclusion: We have discovered a number of interesting derivatives that have encouraging cytokine response data and good metabolic stability, with the potential to have a positive impact on ALS either as single agents, or in combination.

[1]  Xusheng Huang,et al.  Inflammatory Cytokine Levels in Patients with Sporadic Amyotrophic Lateral Sclerosis , 2022, Neurodegenerative Diseases.

[2]  D. Carlisle,et al.  Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated , 2021, Scientific Reports.

[3]  Ali I. Al-Gareeb,et al.  Levamisole Therapy in COVID-19. , 2021, Viral immunology.

[4]  P. Lam,et al.  Advances in Carbon–Element Bond Construction under Chan–Lam Cross-Coupling Conditions: A Second Decade , 2020, Synthesis.

[5]  G. Logroscino,et al.  Plasma Inflammatory Cytokines Are Elevated in ALS , 2020, Frontiers in Neurology.

[6]  F. De Marchi,et al.  Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses , 2020, Brain communications.

[7]  Zhouyang Liu,et al.  Peripheral and Central Nervous System Immune Response Crosstalk in Amyotrophic Lateral Sclerosis , 2020, Frontiers in Neuroscience.

[8]  T. Woodruff,et al.  The Peripheral Immune System and Amyotrophic Lateral Sclerosis , 2020, Frontiers in Neurology.

[9]  Ruth Dorel,et al.  The Buchwald-Hartwig Amination after 25 Years. , 2019, Angewandte Chemie.

[10]  R. Osta,et al.  Are Circulating Cytokines Reliable Biomarkers for Amyotrophic Lateral Sclerosis? , 2019, International journal of molecular sciences.

[11]  M. Swash,et al.  Interleukin-6 and amyotrophic lateral sclerosis , 2019, Journal of the Neurological Sciences.

[12]  K. Roszek,et al.  Purinergic implication in amyotrophic lateral sclerosis—from pathological mechanisms to therapeutic perspectives , 2018, Purinergic Signalling.

[13]  R. Bhandari,et al.  Edaravone: a new hope for deadly amyotrophic lateral sclerosis. , 2018, Drugs of today.

[14]  W. Berger,et al.  Review of cancer treatment with immune checkpoint inhibitors , 2017, Wiener klinische Wochenschrift.

[15]  E. Stommel,et al.  Cytokine expression levels in ALS: A potential link between inflammation and BMAA-triggered protein misfolding. , 2017, Cytokine & growth factor reviews.

[16]  C. Dardis,et al.  Immune Modulation in the Treatment of Amyotrophic Lateral Sclerosis: A Review of Clinical Trials , 2017, Front. Neurol..

[17]  F. Michetti,et al.  The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches , 2017, Front. Aging Neurosci..

[18]  O. Hermine,et al.  ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment? , 2017, Front. Aging Neurosci..

[19]  G. Pazour,et al.  Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness , 2017, Scientific Reports.

[20]  S. Apolloni,et al.  Purinergic contribution to amyotrophic lateral sclerosis , 2016, Neuropharmacology.

[21]  Mrinal Gupta Levamisole: A multi-faceted drug in dermatology , 2016, Indian journal of dermatology, venereology and leprology.

[22]  Helen X. Chen,et al.  Immune checkpoint inhibitors in clinical trials , 2014, Chinese journal of cancer.

[23]  F. Rossi,et al.  The role of microglia in human disease: therapeutic tool or target? , 2014, Acta Neuropathologica.

[24]  J. Bauman,et al.  Immune-Mediated Agranulocytosis Caused by the Cocaine Adulterant Levamisole: A Case for Reactive Metabolite(s) Involvement , 2012, Drug Metabolism and Disposition.

[25]  P. Mccombe,et al.  The Role of Immune and Inflammatory Mechanisms in ALS , 2011, Current molecular medicine.

[26]  L. Kappos,et al.  Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis , 2009, European journal of neurology.

[27]  T. Wiggers,et al.  Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III , 2001, British Journal of Cancer.

[28]  S. Cohen,et al.  Levamisole regulates the proliferation of murine liver T cells through Kupffer-cell-derived cytokines , 1997, Cancer Immunology, Immunotherapy.

[29]  C. Tangen,et al.  Fluorouracil plus Levamisole as Effective Adjuvant Therapy after Resection of Stage III Colon Carcinoma: A Final Report , 1995, Annals of Internal Medicine.

[30]  G. Renoux The General Immunopharmacology of Levamisole , 1980, Drugs.

[31]  C. Niemegeers,et al.  Tetramisole (R 8299), A New, Potent Broad Spectrum Anthelmintic , 1966, Nature.

[32]  M. Merkus,et al.  Levamisole in steroid-sensitive nephrotic syndrome of childhood: the lost paradise? , 2004, Pediatric Nephrology.

[33]  N. Scheinfeld,et al.  Levamisole in Dermatology , 2004, American journal of clinical dermatology.