Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules Adam D. Hughes ⇑ , Kay H. Chin, Sarah L. Dunham, Jeffrey R. Jasper, Kristin E. King, Tae Weon Lee, Mathai Mammen, Jerri Martin, Tod Steinfeld Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA article info Article history: Received 7 September 2010 Revised 11 January 2011 Accepted 12 January 2011 Available online 18 January 2011 Keywords: Multivalent approach Dual pharmacology Muscarinic acetylcholine receptor antagonist Beta 2 adrenoceptor agonist MABA LAMA LABA COPD Bronchodilator Inhaled abstract We sought to design dual pharmacology bronchodilators targeting both the M 3 muscarinic acetylcholine and beta-2 adrenergic (b 2 ) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors. Ó 2011 Published by Elsevier Ltd. Chronic obstructive pulmonary disease (COPD) is the fifth lead- ing cause of death worldwide and its prevalence is thought to be greatly underestimated. 1 COPD is most commonly associated with cigarette smoking; however other risk factors include air pollu- tants and occupational dust, vapors and fumes. This debilitating disease is characterized by a progressive airflow limitation that is not fully reversible. Treatment guidelines emphasize the use of bronchodilators at all stages of the disease with a combination of long-acting bronchodilators recommended for patients with moderate to severe COPD. 2 The addition of an inhaled corticoste- roid (ICS) is recommended for severe and very severe COPD, but recent studies indicate that a broader patient population may benefit from treatment with an ICS in addition to a long-acting bronchodilator. 3 The most frequently used bronchodilators for COPD are inhaled beta-2 adrenergic receptor (b 2 ) agonists and inhaled muscarinic acetylcholine receptor antagonists. Short acting or ‘rescue’ com- pounds with a 2–4 h duration of action, are recommended for the relief of symptoms in patients with mild COPD. Clinical studies have shown that drugs from these two classes may be used effec- tively in combination to provide enhanced efficacy. 4 Combivent Ò consists of a short acting muscarinic antagonist (SAMA) ipratropi- um 5 and a short acting beta agonist (SABA) albuterol 6 formulated in a single inhalation device. Longer acting agents for both mechanisms are also prescribed such as formoterol (1), 7 salmeterol (2) 8 (bid LABAs) and tiotropium (3) 9 (qd LAMA). New once daily LABAs such as indacaterol (4) 10 and GW642444 11 and a twice daily LAMA, aclidinium (5), 12 are in late stage clinical trials. Combination studies with tiotropium and for- moterol have confirmed that the complementary effects of the two mechanisms can provide greater improvements in lung func- tion compared to single agent bronchodilators. 13 Due to the treatment successes of combination products such as Combivent Ò , Advair Ò3 (salmeterol and fluticasone propionate) and Symbicort Ò14 (formoterol and budesonide), it is anticipated that a coformulation of a LABA with a LAMA will soon be available. 15 In this Letter, we describe an alternative approach to obtain dual pharmacology through the design of compounds possessing dual activity as muscarinic antagonists and b 2 agonists (MABAs). By providing both activities in a single molecule, there is the po- tential to provide efficacy comparable to a combination product 0960-894X/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.bmcl.2011.01.043 ⇑ Corresponding author. E-mail address: ahughes@theravance.com (A.D. Hughes). Bioorganic & Medicinal Chemistry Letters 21 (2011) 1354–1358 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl