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.

Scalable Ruthenium-Catalyzed Asymmetric Synthesis of a Key Intermediate for the β2-Adrenergic Receptor Agonist

“…The CBS method is the most widely applied procedure and affords excellent results for a wide range of ketone substrates. Theravance Inc. has reported the use of CBS reduction to prepare several biphenyl derivatives with β2-adrenergic receptor agonist and muscarinic receptor antagonist activity . GSK961081 has been prepared by CBS reduction of ketone…”

A review of recent progress (2002-2012) on the biological activities of pyrazoles

“…One such example 146 began with a novel, selective M3 antagonist 147 which evolved from a nonselective norepinephrine reuptake inhibitor. 149 Compound 148 has high clearance in microsomes and poor membrane permeability, a favorable profile for an inhaled therapeutic.…”

On the Absolute Stereochemistry of Tolterodine: A Circular Dichroism Study

“…Using l -tartaric acid as internal reference, the AC of component 1 in the drug 2 was unambiguously identified as ( R ). Surprisingly enough, this paper has been quoted only five times to date, but never as the proof of the AC of tolterodine [1,17,18,19,20]. As a matter of fact, the correlation between the species investigated by X-ray and those described in the patents is unsure.…”