Adenosine can be phosphorylated by adenosine kinase to form adenosine monophosphate. From there, it is phosphorylated again by adenylate kinase 1 to form adenosine diphosphate, and again by nucleoside diphosphate kinase A or B to form adenosine triphosphate. Alternatively, adenosine can be deaminated by adenosine deaminase to form inosine. Iosine is phosphorylated by purine nucleoside phosphorylase to form hypoxanthine. Hypoxanthine undergoes oxidation by xanthine dehydrogenase twice to form the metabolites xanthine, followed by uric acid.
Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway.
Adenosine is rapidly metabolized intracellularly to the inactive metabolites adenosine monophosphate and inosine ... The drug is cleared by cellular uptake, principally by erythrocytes and vascular endothelial cells, via a specific transmembrane nucleoside transport system.
Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake, ... excessive amounts may be deaminated by an ecto-form of adenosine deaminase.
Adenosine slows conduction time through the AV node and can interrupt the reentry pathways through the AV node, resulting in the restoration of normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White Syndrome. This effect may be mediated through the drug's activation of cell-surface A<sub>1</sub> and A<sub>2</sub> adenosine receptors. Adenosine also inhibits the slow inward calcium current and activation of adenylate cyclase in smooth muscle cells, thereby causing relaxation of vascular smooth muscle. By increasing blood flow in normal coronary arteries with little or no increase in stenotic arteries (with little to no increase in stenotic arteries), adenosine produces a relative difference in thallous (thallium) chloride TI 201 uptake in myocardium supplied by normal verus stenotic coronary arteries.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical.
Novel processes for the preparation of adenosine compounds and intermediates thereto
申请人：——
公开号：US20030069423A1
公开（公告）日：2003-04-10
Novel processes for the preparation of adenosine compounds and intermediates thereto. The adenosine compounds prepared by the present processes may be useful as cardiovascular agents, more particularly as antihypertensive and anti-ischemic agents, as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and as an antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels. The present processes may offer improved yields, purity, ease of preparation and/or isolation of intermediates and final product, and more industrially useful reaction conditions and workability.
[EN] SUBSTITUTED 4-PYRIDONES AND THEIR USE AS INHIBITORS OF NEUTROPHIL ELASTASE ACTIVITY<br/>[FR] 4-PYRIDONES SUBSTITUÉES ET LEUR UTILISATION COMME INHIBITEURS DE L'ACTIVITÉ DE L'ÉLASTASE NEUTROPHILE
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014029831A1
公开（公告）日：2014-02-27
This invention relates to substituted 4-pyridones of formula 1 and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.
SUBSTITUTED 4-PYRIDONES AND THEIR USE AS INHIBITORS OF NEUTROPHIL ELASTASE ACTIVITY
申请人：OOST Thorsten
公开号：US20140057916A1
公开（公告）日：2014-02-27
This invention relates to substituted 4-pyridones of formula 1
and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.
The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.
CHLORO-PYRAZINE CARBOXAMIDE DERIVATIVES WITH EPITHELIAL SODIUM CHANNEL BLOCKING ACTIVITY
申请人：Parion Sciences, Inc.
公开号：US20140171447A1
公开（公告）日：2014-06-19
This invention provides compounds of the formula I:
and their pharmaceutically acceptable salts, useful as sodium channel blockers, compositions containing the same, therapeutic methods and uses for the same and processes for preparing the same.
