Arylpropanolamines: Selective beta sub(3) agonists arising from strategies to mitigate phase I metabolic transformations

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 15; pp. 4290 - 4296
• Main Authors: Washburn, W N, Harper, T W, Wu, G, Godfrey, J D, McCann, P, Girotra, R, Shao, C, Zhang, H, Gavai, A, Mikkilineni, A, Dejneka, T, Ahmed, S, Caringal, Y, Hangeland, J, Zhang, M, Cheng, PTW, Russell, AD, Skwish, S, Slusarchyk, DA, Allen, G T, Frohlich, B H, Abboa-Offei, B E, Cap, M, Waldron, T L, George, R J, Tesfamariam, B, Dickinson, KE, Seymour, A A, Sher, P M
• Format: Journal Article
• Language: English
• Published: 01-08-2007
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.05.030

Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta sub(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha sub(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 beta adrenergic receptors culminated in the identification of the potent, selective beta sub(3) agonist 15f.