title: 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 antagonist and β₂ agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD).
abstract: Through application of our multivalent approach to drug discovery we previously reported the first discovery of dual pharmacology MABA bronchodilators, exemplified by 1. Herein we describe the subsequent lead optimization of both muscarinic antagonist and β2 agonist activities, through modification of the linker motif, to achieve 24 h 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 article culminates with the discovery of our first clinical candidate 12f (TD-5959, GSK961081, batefenterol). In a phase 2b trial, batefenterol produced statistical and clinically significant differences compared to placebo and numerically greater improvements in the primary end point of trough FEV1 compared to salmeterol after 4 weeks of dosing in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Adam D
authors: AD
authors: Hughes
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Yan
authors: Y
authors: Chen
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Sharath S
authors: SS
authors: Hegde
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Jeffrey R
authors: JR
authors: Jasper
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Sarah
authors: S
authors: Jaw-Tsai
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Tae-Weon
authors: TW
authors: Lee
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Alexander
authors: A
authors: McNamara
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: M Teresa
authors: MT
authors: Pulido-Rios
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Tod
authors: T
authors: Steinfeld
authors: Departments of †Medicinal Chemistry, ‡Pharmacology, §Drug Metabolism and Pharmacokinetics, and ∥Molecular and Cellular Biology, Theravance Biopharma, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, United States.
authors: Mathai
authors: M
authors: Mammen
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D002219:Carbamates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003412:Cricetulus; D055808:Drug Discovery; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000187:drug effects*; D008958:Models, Molecular; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D015363:Quinolones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D002219:Carbamates; D018727:Muscarinic Antagonists; D015363:Quinolones; C588122:batefenterol