An Open-label, Randomized, Three-arm Study Evaluating the Potential of BMS-984923 to Alter the Systemic Exposure of Three Orally Administered Probe Substrates in Healthy Adult Participants

The goal of this study is to learn if the investigational drug, BMS-984923 will impact the exposure and clearance of other medications when given together. Most drugs are broken down and cleared in the body via cytochrome P450 enzymes in the liver. The metabolism and clearance of certain drugs can be affected by other drugs when dosed together. To evaluate the impact of BMS-984923 on the clearance of other medications, we will investigate three known pathways which may be impacted by BMS-984923.
In this study participants will take one dose of the three known medications, midazolam, caffeine and dextromethorphan together. These drugs are known to be cleared by different cytochrome P450 enzymes. Blood will be collected to evaluate the exposure and clearance of these medications and their primary metabolites. Study participants will then be administered BMS-984923 for 18-days. On the 18th Day of BMS-984923 dosing, participants will again be co-administering midazolam, caffeine and dextromethorphan. Blood will be collected again, and the concentration of each drug will be measured. We will learn in this study if BMS-984923 changes the exposure and metabolism of the known drugs. These results will inform how BMS-984923 can be administered to patients who take multiple medications.

开始日期2024-11-01

申办/合作机构

Allyx Therapeutics, Inc.初创企业

[+1]

100 项与 Adenosine receptor x A1R x PDE x A2aR 相关的临床结果

登录后查看更多信息

100 项与 Adenosine receptor x A1R x PDE x A2aR 相关的转化医学

登录后查看更多信息

0 项与 Adenosine receptor x A1R x PDE x A2aR 相关的专利（医药）

登录后查看更多信息

项与 Adenosine receptor x A1R x PDE x A2aR 相关的文献（医药）

2017-12-01·Journal of Cheminformatics2区 · 化学

Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases

2区 · 化学

ArticleOA

作者: Bender, Andreas ; Azuaje, Jhonny ; Svensson, Fredrik ; Loza, María I ; Ladds, Graham ; Brea, José ; Mervin, Lewis ; Val, Cristina ; Sotelo, Eddy ; Kalash, Leen ; Zoufir, Azedine ; Glen, Robert

Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. In particular, suitable compounds may be useful in treating neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at the adenosine A₁ and A_2A receptors (A₁R and A_2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible ligands that bind to A₁ and A_2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic approach employing in silico target prediction and docking, which may be generally applicable to multi-target compound design at several target classes. This approach has identified 2-aminopyridine-3-carbonitriles as the first multi-target ligands at A₁R, A_2AR and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efficient one-pot scheme and validated pharmacologically as A₁R/A_2AR-PDE10A ligands, with IC₅₀ values of 2.4-10.0 μM at PDE10A and K_i values of 34-294 nM at A₁R and/or A_2AR. Furthermore, selectivity profiling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested off-targets. In addition, both compounds 8 and 16 exhibited the desired multi-target profile, which could be considered for further functional efficacy assessment, analog modification for the improvement of selectivity towards A₁R, A_2AR and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.