학술논문
Discovery of (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 (TD-5959, GSK961081, Batefenterol):First-in-Class Dual Pharmacology Multivalent Muscarinic Antagonistand β2Agonist (MABA) for the Treatment of ChronicObstructive Pulmonary Disease (COPD)
Document Type
Article
Author
Source
Subject
*MUSCARINIC agents
*OBSTRUCTIVE lung disease treatment
*SALMETEROL
*TOXICOLOGY of poisonous gases
*COMPARATIVE studies
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Language
ISSN
0022-2623
Abstract
Through application of our multivalentapproach to drug discoverywe previously reported the first discovery of dual pharmacology MABAbronchodilators, exemplified by 1. Herein we describethe subsequent lead optimization of both muscarinic antagonist andβ2agonist activities, through modification of thelinker motif, to achieve 24 h duration of action in a guinea pig bronchoprotectionmodel. Concomitantly we targeted high lung selectivities, low systemicexposures and identified crystalline forms suitable for inhalationdevices. This article culminates with the discovery of our first clinicalcandidate 12f(TD-5959, GSK961081, batefenterol). Ina phase 2b trial, batefenterol produced statistical and clinicallysignificant differences compared to placebo and numerically greaterimprovements in the primary end point of trough FEV1 compared to salmeterolafter 4 weeks of dosing in patients with moderate to severe chronicobstructive pulmonary disease (COPD). [ABSTRACT FROM AUTHOR]