Arylpropanolamines: Selective β3 agonists arising from strategies to mitigate phase I metabolic transformations

Abstract Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective β 3 agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01–2% of a very potent α 1 adrenergic agonist 2 . A summary of the SAR for this hepatic microsomal conversion precedes presentation of strategies to maintain the advantages of chemotype 1 while mitigating the consequences of N-dealkylation. This effort led to the identification of 4-hydroxy-3-methylsulfonanilidopropanolamines 15 for which the SAR for the unique stereochemical requirements for binding to the β adrenergic receptors culminated in the identification of the potent, selective β 3 agonist 15f .