Through application of our multivalent approach to drug discovery we previously reported the first discovery of dual pharmacology MABA bronchodilators, exemplified by THRX-198321. Herein we describe the subsequent lead optimization of both muscarinic antagonist and �2 agonist activities, through modification of the linker motif, to achieve 24h duration of action in a guinea pig bronchoprotection model. Concomitantly, we targeted high lung selectivities, low systemic exposures and identified crystalline forms suitable for inhalation devices. This presentation culminates with the discovery of our first clinical candidate TD-5959 (GSK-961081). In a Phase 2b trial, TD-5959 produced statistical and clinically significant differences compared to placebo and numerically greater improvements in the primary endpoint of trough FEV1compared to salmeterol after 4 weeks of dosing in patients with moderate to severe COPD.

Discovery of TD-5959 (GSK-961081): A first-in-class dual pharmacology multivalent muscarinic antagonist and beta-2 agonist (MABA) for the treatment of COPD

248th National Meeting (2014)

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