Doxofylline

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Brochodilators

Insoluble

>39.9 [ug/mL] (The mean of the results at pH 7.4)

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P264+P265, P270, P280, P301+P317, P302+P352, P305+P351+P338, P321, P330, P332+P317, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

R - Respiratory system

QR - Respiratory system

Doxofylline is a methylxanthine bronchodilator with potent bronchodilator activity comparable to that of theophylline. In animal studies, doxofylline demonstrated to attenuate bronchoconstriction, inflammatory actions and the release of thromboxane A2 (TXA2) when challenged with platelet-activating factor. Doxofylline does not demonstrate direct inhibition of any histone deacetylase (HDAC) enzymes or known PDE enzyme isoforms and did not act as an antagonist at A2 or A2 receptors. The affinity for adenosine A1, A2A and A2B receptors are reported to be all higher than 100 µM. It only displays an inhibitory action against PDE2A1 and antagonism at adenosine A(2A) at high concentrations. A study demonstrated that doxofylline interacts with β2-adrenoceptors to induce blood vessel relaxation and airway smooth muscle relaxation. In dog studies, doxofylline decreased airway responsiveness at a dose that did not affect heart rate and respiratory rate.

The main mechanism of action of doxofylline is unclear. One of the mechanisms of action of is thought to arise from the inhibition of phosphodiesterase activity thus increasing the levels of cAMP and promoting smooth muscle relaxation. The interaction of doxofylline with beta-2 adrenoceptors was demonstrated by a study using nonlinear chromatography, frontal analysis and molecular docking. Serine 169 and serine 173 residues in the receptor are thought to be critical binding sites for doxofylline where hydrogen bonds are formed. Via mediating the actions of beta-2 adrenoceptors, doxofylline induces blood vessel relaxation and airway smooth muscle relaxation. There is also evidence that doxofylline may exert anti-inflammatory actions by reducing the pleurisy induced by the inflammatory mediator platelet activating factor (PAF) according to a rat study. It is suggested that doxofylline may play an important role in attenuating leukocyte diapedesis, supported by mouse preclinical studies where doxofylline administration was associated with inhibited leukocyte migration across vascular endothelial cells in vivo and in vitro.Unlike theophylline, doxofylline does not inhibit tumor necrosis factor-induced interleukin (IL)-8 secretion in ASM cells.