title: Molecular hybridization yields triazole bronchodilators for the treatment of COPD.
abstract: A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
authors.affiliation: WorldWide Medicinal Chemistry, 610 Main Street, Cambridge, MA 02139, USA. Electronic address: lyn.jones@pfizer.com.
authors.forename: Lyn H
authors.initials: LH
authors.lastname: Jones
authors.affiliation: Pharmaceutical Sciences, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Burrows
authors.affiliation: Pharmaceutical Sciences, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Feeder
authors.affiliation: WorldWide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Glossop
authors.affiliation: WorldWide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: James
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Rhys M
authors.initials: RM
authors.lastname: Jones
authors.affiliation: WorldWide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Kenyon
authors.affiliation: Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK; CVMED Research Unit, Pfizer, Cambridge, MA 02139, USA.
authors.forename: Sheena
authors.initials: S
authors.lastname: Patel
authors.affiliation: WorldWide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Dannielle F
authors.initials: DF
authors.lastname: Roberts
authors.affiliation: WorldWide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Selby
authors.affiliation: WorldWide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Ross S
authors.initials: RS
authors.lastname: Strang
authors.affiliation: Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Emilio F
authors.initials: EF
authors.lastname: Stuart
authors.affiliation: Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Trevethick
authors.affiliation: Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Watson
authors.affiliation: Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Wright
authors.affiliation: Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK; Inflammation and Immunology Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Clarke
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D009241:Ipratropium / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D051381:Rats; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors; D000068299:Salmeterol Xinafoate / Q000494:pharmacology; D000069447:Tiotropium Bromide / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; C000609106:PF-04810097; D043587:Receptor, Muscarinic M3; D014230:Triazoles; D000068299:Salmeterol Xinafoate; D009241:Ipratropium; D000069447:Tiotropium Bromide
keywords: Bifunctional; Bronchodilator; COPD; Inhalation by design; MABA