- |||||||||| namodenoson (CF102) - Can / Fite, CGS 21680 / Novartis
Journal: The different effects of four adenosine receptors in liver fibrosis. (Pubmed Central) - Sep 20, 2024
Additionally, 5'-N-ethyl-carboxamidoadenosine (NECA), a metabolically stable adenosine analog, alleviated liver fibrosis and inhibited LX2 cell activity, proliferation, and migration. This study demonstrated the different roles of A1R/A2AR/A2BR/A3R during liver fibrosis development via regulating the HSC activity and proliferation.
- |||||||||| namodenoson (CF102) - Can / Fite
Journal: Neuroprotective compounds alter the expression of genes coding for proteins related to mitochondrial function in activated microglia. (Pubmed Central) - Sep 11, 2024
In this research, we analyzed by RNAseq the gene expression in activated microglia treated with an adenosine A2A receptor antagonist, SCH 582561, and/or an A3 receptor agonist, 2-Cl-IB-MECA, since these receptors are deeply related to neurodegeneration and inflammation...Additionally, we evaluated the oxygen consumption rate (OCR) of mitochondria in microglia treated with LPS and IFN-?, both alone and in combination with adenosinergic compounds. The data showed an improvement in mitochondrial function with the antagonist of the adenosine A2A receptor, compared to the effects of pro-inflammatory stimulus, confirming a functional effect consistent with the RNAseq data.
- |||||||||| namodenoson (CF102) - Can / Fite
Trial initiation date, Metastases: CF102-222PC: Namodenoson Treatment of Advanced Pancreatic Cancer (clinicaltrials.gov) - Aug 21, 2024
P2, N=20, Not yet recruiting,
In addition, we demonstrated the previously uncharacterized allosteric signaling-enhancing effect of LUF6000 in cells endogenously expressing the hA3AR. Initiation date: Jul 2024 --> Dec 2024
- |||||||||| namodenoson (CF102) - Can / Fite
Journal: Lipid Trolling to Optimize A3 Adenosine Receptor-Positive Allosteric Modulators (PAMs). (Pubmed Central) - Jul 26, 2024
The putative mechanism involves a flexible, terminally cationic chain penetrating the lipid environment for stable electrostatic anchoring to cytosolic phospholipid head groups, suggesting "lipid trolling", supported by molecular dynamic simulation of the active-state model. Thus, we have improved A3AR PAM activity through rational design based on an extrahelical, lipidic binding site.
- |||||||||| namodenoson (CF102) - Can / Fite, piclidenoson (CF101) - Can / Fite
Review, Journal: Adenosine A3 Receptor: From Molecular Signaling to Therapeutic Strategies for Heart Diseases. (Pubmed Central) - Jun 19, 2024
Several A3AR-specific agonists, such as piclidenoson and namodenoson, exert cardioprotective impacts during ischemia in the diverse animal models of heart disease. Thus, modulating A3ARs serves as a potential therapeutic approach, fueling considerable interest in developing compounds that target A3ARs as potential treatments for heart diseases.
- |||||||||| namodenoson (CF102) - Can / Fite
Journal: Gene regulation in activated microglia by adenosine A receptor agonists: a transcriptomics study. (Pubmed Central) - Jun 18, 2024
Analysis of known and predicted protein-protein interactions showed that Smad3 and Sp1 are transcription factors whose genes are regulated by AR activation. Under the conditions of cell activation and agonist treatment regimen, 2-Cl-IB-MECA did not lead to any tendency to favor the expression of genes related to neuroprotective microglia (M2).
- |||||||||| namodenoson (CF102) - Can / Fite
Review, Journal: Namodenoson at the Crossroad of Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma. (Pubmed Central) - Apr 27, 2024
Subsequently, inhibition of liver inflammation, steatosis, and fibrosis were documented in MASH experimental models, and inhibition of HCC growth was observed in vitro, in vivo, and in clinical studies. This review discusses the evidence related to the multifaceted mechanism of action of namodenoson, and how this mechanism is reflected in the available clinical data in MASH and HCC.
- |||||||||| namodenoson (CF102) - Can / Fite
Lipid trolling to optimize A3 adenosine receptor positive allosteric modulators (PAMs) | Poster Board #1734 (In-person; Poster Board #1734; Hall C (Ernest N. Morial Convention Center)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_2978;
This review discusses the evidence related to the multifaceted mechanism of action of namodenoson, and how this mechanism is reflected in the available clinical data in MASH and HCC. For example, compound MRS8247, containing eight methylenes, at 100 nM increased both E max and potency of agonist (Cl-IB-MECA) in [ 35 S]GTPgS binding...Among imidazole-modified heterocycles, [1,3]thiazolo[4,5-c]quinoline-4-amines retained moderate PAM effect without a right shift of the agonist activation curves up to 10
- |||||||||| namodenoson (CF102) - Can / Fite
Journal: First Potent Macrocyclic A Adenosine Receptor Agonists Reveal G-Protein and ?-Arrestin2 Signaling Preferences. (Pubmed Central) - Sep 14, 2023
Functional hAAR comparison of two sets of open/closed analogues in ?-arrestin2 and G protein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA 1...This example of macrocyclization altering the coupling pathways of small-molecule (nonpeptide) GPCR agonists is the first for potent and selective macrocyclic AR agonists. These initial macrocyclic derivatives can serve as a guide for the future design of macrocyclic AR agonists displaying unanticipated pharmacology.
- |||||||||| piclidenoson (CF101) - Can / Fite, Cipher, China Medical System
CF101. Controversies in High-Risk Anesthesia and Critical Care (South: 201/202) - Jul 20, 2023 - Abstract #ASA2023ASA_24;
Session Learning Objective 2: Review existing literature regarding those decisions. Session Learning Objective 3: Integrate literature, audience participation, clinical factors and expert opinion as bases for clinical decision making.
- |||||||||| piclidenoson (CF101) - Can / Fite, Cipher, China Medical System
DG03--What's the Play Coach?- The Pharmacy Team Playbook for CF (Team Pharmacy CF 101) (127 A-C (North)) - Jul 9, 2023 - Abstract #NACFC2023NACFC_9;
Learning Objectives: Discuss current cystic fibrosis pharmacotherapy and understand roles in therapy. Analyze new and changing roles and responsibilities for pharmacists and pharmacy technicians.Formulate strategies to navigate current medication access challenges and foster medication adherence.
- |||||||||| namodenoson (CF102) - Can / Fite
Trial completion date, Trial primary completion date: Namodenoson in the Treatment of Non-Alcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - Jun 18, 2023
P2b, N=114, Recruiting,
Analyze new and changing roles and responsibilities for pharmacists and pharmacy technicians.Formulate strategies to navigate current medication access challenges and foster medication adherence. Trial completion date: Apr 2023 --> Oct 2025 | Trial primary completion date: Apr 2023 --> Apr 2025
- |||||||||| namodenoson (CF102) - Can / Fite
Effects of namodenoson on pancreatic carcinoma: Preclinical evidence. () - Apr 26, 2023 - Abstract #ASCO2023ASCO_4827;
Our findings showed that nanomolar concentrations of namodenoson inhibit the growth of pancreatic carcinoma via A3AR activation and de-regulation of the Wnt/?-catenin pathway, both as a monotherapy and in combination with gemcitabine. Thus, these results support a potential role for namodenoson in treating pancreatic cancer, thereby opening a novel therapeutic opportunity for this disease.
- |||||||||| namodenoson (CF102) - Can / Fite
First potent macrocyclic A3 adenosine receptor agonists having preferences for G-protein and b-arrestin2 signaling (Hall F-H (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_2824;
Functional hA3AR comparison of two sets of open/closed analogues in b-arrestin2 and Gi/o protein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA 1...This example of macrocyclization altering the coupling pathways of small molecule (non-peptide) GPCR agonists is the first for potent and selective macrocyclic AR agonists. These initial macrocyclic derivatives can serve as a guide for the future design of macrocyclic AR agonists displaying unanticipated pharmacology.
- |||||||||| namodenoson (CF102) - Can / Fite
Award Address (E. B. Hershberg Award for Important Discoveries in_x000D_ Medicinally Active Substances sponsored by Merck Research Laboratories). Purinergic signaling modulators for chronic disease treatment (Sagamore Ballroom 2 (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_1957;
We have introduced many selective purinergic receptor ligands as pharmacological probes and clinical candidate molecules for treating autoimmune inflammatory diseases, ischemia, cancer, pain, etc. Our prototypical A3AR agonists (IB-MECA, piclodenoson and Cl-IB-MECA, namodenoson) are safe and efficacious in advanced clinical trials for psoriasis and liver diseases...Either P2Y6R or P2Y14R selective knockout in mouse adipocytes induces in vivo metabolic protection in obesity model, suggesting that antagonists of either subtype are potentially useful for treating diabetes and obesity. Thus, modulation of the purinergic signaling network has broad potential for treating chronic diseases, and both structural and empirical approaches to ligand discovery are productive, leading to multiple clinical trials.
- |||||||||| CF602 - Can / Fite
Preclinical, Journal: A3 adenosine receptor allosteric modulator CF602 reverses erectile dysfunction in a diabetic rat model. (Pubmed Central) - Sep 10, 2022
A significant increase in smooth muscle:collagen ratio, vascular endothelial growth factor and endothelial nitric oxide synthase was also observed in both administration modes. In conclusion, topical and oral treatment with CF602 significantly improved erectile function, supporting its further evaluation as a treatment for ED.
- |||||||||| namodenoson (CF102) - Can / Fite
COMPLETE RESPONSE INDUCED BY NAMODENOSON IN ADVANCED HEPATOCELLULAR CARCINOMA: A CASE REPORT () - Aug 31, 2022 - Abstract #ILCA2022ILCA_236;
P2
The patient was in the namodenoson arm and continued treatment with namodenoson for 5 years under an open label extension program (treatment is ongoing). Alanine transaminase (ALT) and aspartate aminotransferase (AST) levels that were elevated at baseline (68 U/L and 44 U/L, respectively) normalized after 1 treatment cycle, and normal levels were maintained for 5 years.
- |||||||||| namodenoson (CF102) - Can / Fite, piclidenoson (CF101) - Can / Fite, Cipher, China Medical System
Review, Journal: Drugs Targeting the A3 Adenosine Receptor: Human Clinical Study Data. (Pubmed Central) - Jul 1, 2022
A phase IIb study in NASH is currently enrolling patients. In conclusion, A3AR agonists are promising drug candidates in advanced stages of clinical development and demonstrate safety and efficacy in their targeted indications.
- |||||||||| piclidenoson (CF101) - Can / Fite, Cipher, China Medical System
Trial completion: CF101 Therapy in Patients With Moderate-to-severe Plaque Psoriasis (clinicaltrials.gov) - Jun 28, 2022
P3, N=528, Completed,
In conclusion, A3AR agonists are promising drug candidates in advanced stages of clinical development and demonstrate safety and efficacy in their targeted indications. Active, not recruiting --> Completed
- |||||||||| evodenoson (ATL313) / AbbVie, namodenoson (CF102) - Can / Fite
Adenosine Receptors Differentially Mediate Enteric Glial Cell Death And Proinflammatory Response Induced By Clostridioides Difficile Toxins A And B (Exhibit and Poster Hall) - Jun 4, 2022 - Abstract #ASMMicrobe2022ASM_Microbe_3136;
A2A agonist (ATL313), but not A2A antagonist (SCH58261), decreased (p<0.001) apoptosis as detected by the formation of Phosphatidylserine-annexin binding and caspase 3/7 activity induced by TcdA and TcdB in EGCs...A3 agonist (Cl-IBMECA), but not A3 blocker (MRS1220), reduced apoptosis in EGCs challenged with TcdA and TcdB...In vivo, infected A2B KO mice, but not A2A, exhibited a lower percentage of S100B+TUNEL+cells compared to infected WT mice (p<0.0001). Our findings indicate that EGCs elicit a protective anti-inflammatory, via activation of A2A, A2B and A3, and anti-apoptotic, via upregulation of A2A and A3 and downregulation of A2B, responses against C. difficile toxins.
- |||||||||| namodenoson (CF102) - Can / Fite
Journal: Characterization of Novel A Adenosine Receptor Allosteric Modulators. (Pubmed Central) - May 14, 2022
We have identified improved PAMs for the human A receptor that: 1) not only increase agonist efficacy, but also increase agonist potency (and binding affinity), and 2) may bias receptor signaling towards G protein-dependent signaling. Furthermore, we have evidence supporting a novel intracellular allosteric binding pocket on the A AR.
- |||||||||| namodenoson (CF102) - Can / Fite, CGS 21680 / Novartis
Journal: The Role of Selective Adenosine Receptor Ligands on Inflammatory Pain. (Pubmed Central) - May 14, 2022
However, both the A1 selective agonist (±)-5'-Chloro-5'-deoxy-ENBA, and the A3 selective agonist 2-Cl-IB-MECA produced a significant reversal of the PWT at the highest dose of 1 mg/kg, suggesting antinociceptive effects of the A1 and A3 adenosine receptors...Both the A2A selective antagonist ZM 241385 and the A2B selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. In conclusion, A1, A2A, A2B and A3 adenosine receptors are involved in mediating inflammatory pain states, and represent promising targets for the treatment of chronic pain conditions.
- |||||||||| piclidenoson (CF101) - Can / Fite, Cipher, China Medical System
Trial completion: Piclidenoson for Treatment of COVID-19 (clinicaltrials.gov) - Apr 22, 2022
P2, N=6, Completed,
In conclusion, A1, A2A, A2B and A3 adenosine receptors are involved in mediating inflammatory pain states, and represent promising targets for the treatment of chronic pain conditions. Active, not recruiting --> Completed
- |||||||||| namodenoson (CF102) - Can / Fite
Journal: Intraocular implants loaded with AR agonist rescue retinal ganglion cells from ischemic damage. (Pubmed Central) - Apr 12, 2022
We further demonstrated that 2-Cl-IB-MECA-loaded PCL implants were able to enhance RGC function that was compromised by transient ischemia. Taking into consideration the beneficial effects afforded by 2-Cl-IB-MECA released from the PCL implant, this can be envisaged a good therapeutic strategy to protect RGCs.
- |||||||||| namodenoson (CF102) - Can / Fite
Preclinical, Journal: 2‑Cl‑IB‑MECA regulates the proliferative and drug resistance pathways, and facilitates chemosensitivity in pancreatic and liver cancer cell lines. (Pubmed Central) - Apr 5, 2022
Notably, experiments with AAR‑specific antagonist, N‑[9‑Chloro‑2‑(2‑furanyl)(1,2,4)‑triazolo(1,5‑c)quinazolin‑5‑yl]benzene acetamide, revealed that 2‑Cl‑IB‑MECA had antitumor effects via both A3AR‑dependent and ‑independent pathways. In conclusion, the present study identified novel antitumor mechanisms of 2‑Cl‑IB‑MECA in pancreatic and hepatocellular carcinoma in vitro that further underscores the importance of A3AR agonists in cancer therapy.
- |||||||||| namodenoson (CF102) - Can / Fite
Review, Journal: Therapeutic Potential of Highly Selective A Adenosine Receptor Ligands in the Central and Peripheral Nervous System. (Pubmed Central) - Apr 2, 2022
This review places particular focus on brain ischemia insults and colitis, where the prototypical AR agonist, Cl-IB-MECA, and antagonist, MRS1523, have been used in research studies as reference compounds to explore the effects of latest-generation ligands on this receptor. The advantages and weaknesses of these compounds in terms of therapeutic potential are discussed.
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