title: Arylpropanolamines: selective beta3 agonists arising from strategies to mitigate phase I metabolic transformations.
abstract: Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha(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(3) agonist 15f.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. William.Washburn@bms.com
authors.forename: W N
authors.initials: WN
authors.lastname: Washburn
authors.forename: T W
authors.initials: TW
authors.lastname: Harper
authors.forename: G
authors.initials: G
authors.lastname: Wu
authors.forename: J D
authors.initials: JD
authors.lastname: Godfrey
authors.forename: P
authors.initials: P
authors.lastname: McCann
authors.forename: R
authors.initials: R
authors.lastname: Girotra
authors.forename: C
authors.initials: C
authors.lastname: Shao
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Gavai
authors.forename: A
authors.initials: A
authors.lastname: Mikkilineni
authors.forename: T
authors.initials: T
authors.lastname: Dejneka
authors.forename: S
authors.initials: S
authors.lastname: Ahmed
authors.forename: Y
authors.initials: Y
authors.lastname: Caringal
authors.forename: J
authors.initials: J
authors.lastname: Hangeland
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: P T W
authors.initials: PT
authors.lastname: Cheng
authors.forename: A D
authors.initials: AD
authors.lastname: Russell
authors.forename: S
authors.initials: S
authors.lastname: Skwish
authors.forename: D A
authors.initials: DA
authors.lastname: Slusarchyk
authors.forename: G T
authors.initials: GT
authors.lastname: Allen
authors.forename: B H
authors.initials: BH
authors.lastname: Frohlich
authors.forename: B E
authors.initials: BE
authors.lastname: Abboa-Offei
authors.forename: M
authors.initials: M
authors.lastname: Cap
authors.forename: T L
authors.initials: TL
authors.lastname: Waldron
authors.forename: R J
authors.initials: RJ
authors.lastname: George
authors.forename: B
authors.initials: B
authors.lastname: Tesfamariam
authors.forename: K E
authors.initials: KE
authors.lastname: Dickinson
authors.forename: A A
authors.initials: AA
authors.lastname: Seymour
authors.forename: P M
authors.initials: PM
authors.lastname: Sher
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000494:pharmacology*; D000478:Alkylation; D010084:Oxidation-Reduction; D011412:Propanolamines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D011412:Propanolamines