tolterodine and Pulmonary-Disease--Chronic-Obstructive

This paper describes the successful design and development of dual pharmacology β-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Animals; Benzhydryl Compounds; Cresols; Drug Design; Drug Therapy, Combination; Guinea Pigs; Molecular Structure; Muscarinic Antagonists; Phenylpropanolamine; Pulmonary Disease, Chronic Obstructive; Tolterodine Tartrate

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.

Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic Uptake Inhibitors; Animals; Bronchoconstriction; Bronchodilator Agents; Caco-2 Cells; Cell Membrane Permeability; Guinea Pigs; Humans; In Vitro Techniques; Microsomes, Liver; Models, Molecular; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M3; Structure-Activity Relationship; Trachea