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Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and ß2-adrenoceptor agonist properties.
Hegde, Sharath S; Hughes, Adam D; Chen, Yan; Steinfeld, Tod; Jasper, Jeffrey R; Lee, Tae-Weon; McNamara, Alexander; Martin, William J; Pulido-Rios, M Teresa; Mammen, Mathai.
Afiliação
  • Hegde SS; Theravance, Inc., South San Francisco, California shegde@theravance.com.
  • Hughes AD; Theravance, Inc., South San Francisco, California.
  • Chen Y; Theravance, Inc., South San Francisco, California.
  • Steinfeld T; Theravance, Inc., South San Francisco, California.
  • Jasper JR; Theravance, Inc., South San Francisco, California.
  • Lee TW; Theravance, Inc., South San Francisco, California.
  • McNamara A; Theravance, Inc., South San Francisco, California.
  • Martin WJ; Theravance, Inc., South San Francisco, California.
  • Pulido-Rios MT; Theravance, Inc., South San Francisco, California.
  • Mammen M; Theravance, Inc., South San Francisco, California.
J Pharmacol Exp Ther ; 351(1): 190-9, 2014 Oct.
Article em En | MEDLINE | ID: mdl-25100753
The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and ß2-adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM2 (Ki = 1.4 nM), hM3 muscarinic receptors (Ki = 1.3 nM) and hß2-adrenoceptors (Ki = 3.7 nM). GSK-961081 behaved as a potent hß2-adrenoceptor agonist (EC50 = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hß1- and hß3-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. Significant bronchoprotective effects of GSK-961081 were evident in guinea pigs via MA, BA, and MABA mechanisms for up to 7 days after dosing. The lung selectivity index of GSK-961081 in guinea pigs was 55- to 110-fold greater than that of tiotropium with respect to systemic antimuscarinic antisialagogue effects and was 10-fold greater than that of salmeterol with respect to systemic ß2-adrenoceptor hypotensive effects. These preclinical findings studies suggest that GSK-961081 has the potential to be a promising next-generation inhaled lung-selective bronchodilator for the treatment of airway diseases, including chronic obstructive pulmonary disease.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Broncodilatadores / Carbamatos / Quinolonas / Antagonistas Muscarínicos / Antagonistas de Receptores Adrenérgicos beta 2 Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Broncodilatadores / Carbamatos / Quinolonas / Antagonistas Muscarínicos / Antagonistas de Receptores Adrenérgicos beta 2 Idioma: En Ano de publicação: 2014 Tipo de documento: Article