生物活性

• 描述Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition that is characterized by progressive airflow limitation caused by a mixture of small airway disease and parenchymal destruction. β₂-adrenoceptor agonists (BAs) and muscarinic receptor antagonists (MAs), are currently available for use in the treatment of COPD. GSK-961081 is a novel first-in-class inhaled bifunctional compound possessing both MA and BA properties (MABA). GSK-961081 displayed high affinity for hM₂ (K_i = 1.4 nM), hM₃ muscarinic receptors (K_i = 1.3 nM) and hβ₂-adrenoceptors (K_i = 3.7 nM). GSK-961081 behaved as a potent hβ2-adrenoceptor agonist (EC₅₀ = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hβ₁- and hβ₃-adrenoceptors, respectively. In guinea pig isolated tracheal tissues, GSK-961081 produced smooth muscle relaxation through MA (EC₅₀ = 50.2 nM), BA (EC₅₀ = 24.6 nM), and MABA (EC₅₀ = 11 nM) mechanisms. In the guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MA (ED₅₀ = 33.9 µg/ml), BA (ED₅₀ = 14.1 µg/ml), and MABA (ED₅₀ = 6.4 µg/ml) mechanisms^[3].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01449799	Pulmonary Disease, Chronic Obs... more >>tructive Collapse <<	Phase 1	Completed	-	United Kingdom ... more >> GSK Investigational Site London, United Kingdom, NW10 7EW Collapse <<
  NCT02573870	-	-	Completed	-	-
  NCT02570165	Pulmonary Disease, Chronic Obs... more >>tructive Collapse <<	Phase 2	Completed	-	United States, Florida ... more >> GSK Investigational Site Hialeah, Florida, United States, 33013 United States, Maryland GSK Investigational Site Baltimore, Maryland, United States, 21225 United States, Missouri GSK Investigational Site Saint Louis, Missouri, United States, 63141-6361 United States, Oregon GSK Investigational Site Medford, Oregon, United States, 97504 United States, South Carolina GSK Investigational Site Anderson, South Carolina, United States, 29621 GSK Investigational Site Greenville, South Carolina, United States, 29615 GSK Investigational Site Simpsonville, South Carolina, United States, 29681 GSK Investigational Site Spartanburg, South Carolina, United States, 29303 GSK Investigational Site Union, South Carolina, United States, 29379 Germany GSK Investigational Site Ruedersdorf, Brandenburg, Germany, 15562 GSK Investigational Site Frankfurt, Hessen, Germany, 60596 GSK Investigational Site Wiesbaden, Hessen, Germany, 65187 GSK Investigational Site Grosshansdorf, Schleswig-Holstein, Germany, 22927 GSK Investigational Site Luebeck, Schleswig-Holstein, Germany, 23552 GSK Investigational Site Berlin, Germany, 10119 GSK Investigational Site Berlin, Germany, 10717 GSK Investigational Site Berlin, Germany, 10787 GSK Investigational Site Hamburg, Germany, 22299 South Africa GSK Investigational Site Port Elizabeth, Eastern Cape, South Africa, 6001 GSK Investigational Site Middelburg, Mpumalanga, South Africa, 1050 GSK Investigational Site Bellville, South Africa, 7530 GSK Investigational Site Bloemfontein, South Africa, 9301 GSK Investigational Site Meyerspark/ Pretoria, South Africa, 184 GSK Investigational Site Mowbray, South Africa, 7700 GSK Investigational Site Somerset West, South Africa, 7130 GSK Investigational Site Thabazimbi, South Africa Collapse <<

• 更多
• 参考文献

• [1] Mastrodicasa MA, Droege CA, et al. Long acting muscarinic antagonists for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs. Expert Opin Investig Drugs. 2017 Feb;26(2):161-174.

  [2] Hegde SS, Hughes AD, et al. Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and β2-adrenoceptor agonist properties. J Pharmacol Exp Ther. 2014 Oct;351(1):190-9.

  [3] Hegde SS, Hughes AD, Chen Y, et al. Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and β2-adrenoceptor agonist properties. J Pharmacol Exp Ther. 2014;351(1):190‐199