In Vitro, In Silico, and In Vivo Assessments of Pharmacokinetic Properties of ZM241385

Abstract

Parkinson’s disease is one of the most common neurodegenerative diseases. Adenosine regulates the response to other neurotransmitters in the brain regions related to motor function. In the several subtypes of adenosine receptors, especially, adenosine 2A receptors (A2ARs) are involved in neurodegenerative conditions. ZM241385 is one of the selective non-xanthine A2AR antagonists with high affinity in the nanomolar range. This study describes the in vitro and in vivo pharmacokinetic properties of ZM241385 in rats. A liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qToF MS) method was developed for the determination of ZM241385 in rat plasma. In vivo IV administration studies showed that ZM241385 was rapidly eliminated in rats. However, the result of in vitro metabolic stability studies showed that ZM241385 had moderate clearance, suggesting that there is an extra clearance pathway in addition to hepatic clearance. In addition, in vivo PO administration studies demonstrated that ZM241385 had low exposure in rats. The results of semi-mass balance studies and the in silico PBPK modeling studies suggested that the low bioavailability of ZM241385 after oral administration in rats was due to the metabolism and by liver, kidney, and gut.

Improvement of the sepsis survival rate by adenosine 2a receptor antagonists depends on immune regulatory functions of regulatory T-cells

“…Adenosine is one of the oldest organic molecules on Earth, having appeared > 100 million years before the birth of the first living form ( 45 , 46 ). Pharmacology intervention of A2aRs has been used clinically in several conditions; for example, an A2aR agonist has been used in myocardial perfusion imaging ( 47 ), and an A2aR antagonist has been used in Parkinson’s disease ( 48 , 49 ). In this study, we used an A2aR antagonist for the treatment of polymicrobial sepsis and found that the survival of our CLP mouse model was improved by ZM241385.…”

Multifunctional Lipid Bilayer Nanocarriers for Cancer Immunotherapy in Heterogeneous Tumor Microenvironments, Combining Immunogenic Cell Death Stimuli with Immune Modulatory Drugs

“…A number of A2AR antagonists have emerged for cancer immunotherapy, including SMI with xanthine or non-xanthine structures for launching therapeutic intervention in solid tumors in animals and clinical trials in humans. , This includes the use of the non-xanthine antagonist, ZM241385, to suppress tumor growth and metastases in TNBC or colon cancer preclinical models . ZM241385 has low bioavailability during oral administration . Our use of medicinal chemistry criteria to identify A2AR antagonists that could be delivered as lipid-conjugated prodrugs, demonstrated a phenolic hydroxyl group on ZM241385 for conjugation to several lipid moieties (Figure ).…”

“…This includes the availability of ester or ether linkages to terminal hydroxyls on fatty alcohol or cholesterol, as well as conjugation to the carboxyl terminal groups on fatty acids, DGS derivatives, and CHEMS. Bilayer incorporation of these prodrugs not only offers to improve the unfavorable drug PK seen in oral administration but also allows development of coformulated carriers. There is indeed strong rationale to consider combining A2AR antagonists with chemotherapy, radiation therapy or PD-1/PD-L1 and CTLA-4 checkpoint blockade .…”

“…This enables synthesis of ester or ether drug linkages to fatty alcohols or cholesterol, as well as the possibility to conjugate the drug to fatty acid, DGS, or CHEMS carboxyl terminal groups. Not only does bilayer incorporation of these drug conjugates offer improvement of the unfavorable drug PK, 195 but it also allows the development of coformulated multidrug carriers. D.5.…”

Structure-Based Design of Dual-Acting Compounds Targeting Adenosine A2A Receptor and Histone Deacetylase as Novel Tumor Immunotherapeutic Agents

“…Compound 18f showed no significant oral absorption (data not shown), and compound 35b exhibited low drug exposure after oral administration (Table 4). Because both compounds ZM-241385 and SCH-58261 showed extremely low bioavailability in previous studies, 40,41 the nitrogen-rich bicyclic and tricyclic core structures might be the main reason for the poor permeability and PK properties of these compounds. Compound 24e, to our delight, showed an acceptable oral exposure and a bioavailability of 30.3% in ICR mice.…”