title: Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonist-β₂-agonist for the treatment of chronic obstructive pulmonary disease.
abstract: Following interrogation of a wide-ligand profile database, a nonselective norepinephrin reuptake inhibitor was converted into a novel muscarinic antagonist using two medicinal chemistry transformations (M3/NRI selectivity of >1000). Conjugation to a β(2) agonist motif furnished a molecule with balanced dual pharmacology, as demonstrated in a guinea pig trachea tissue model of bronchoconstriction. This approach provides new starting points for the treatment of chronic obstructive pulmonary disease and illustrates the potential for building selectivity into GPCR modulators that possess intrinsic promiscuity or reverse selectivity.
authors.affiliation: WorldWide Medicinal Chemistry, Pfizer R&D, Ramsgate Road, Sandwich, Kent, CT13 9NJ, U.K.
authors.forename: Rachel
authors.initials: R
authors.lastname: Osborne
authors.forename: Nick
authors.initials: N
authors.lastname: Clarke
authors.forename: Paul
authors.initials: P
authors.lastname: Glossop
authors.forename: Amy
authors.initials: A
authors.lastname: Kenyon
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Sheena
authors.initials: S
authors.lastname: Patel
authors.forename: Susan
authors.initials: S
authors.lastname: Summerhill
authors.forename: Lyn H
authors.initials: LH
authors.lastname: Jones
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D043587:Receptor, Muscarinic M3 / Q000502:physiology*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3