Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonist-beta(2)-agonist for the treatment of chronic obstructive pulmonary disease.

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Osborne R, Clarke N, Glossop P, Kenyon A, Liu H, Patel S, Summerhill S, Jones LH

Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonist-beta(2)-agonist for the treatment of chronic obstructive pulmonary disease.

J Med Chem. 2011 Oct 13;54(19):6998-7002. doi: 10.1021/jm2007535. Epub 2011 Sep 2.

PubMed ID

21863888 [ View in PubMed

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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 beta(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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Tolterodine	Muscarinic acetylcholine receptor M3	Ki (nM)	3.6	N/A	N/A	Details