Arylpropanolamines: selective beta3 agonists arising from strategies to mitigate phase I metabolic transformations.
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.
Washburn
W N
WN
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. William.Washburn@bms.com
Harper
T W
TW
Wu
G
G
Godfrey
J D
JD
McCann
P
P
Girotra
R
R
Shao
C
C
Zhang
H
H
Gavai
A
A
Mikkilineni
A
A
Dejneka
T
T
Ahmed
S
S
Caringal
Y
Y
Hangeland
J
J
Zhang
M
M
Cheng
P T W
PT
Russell
A D
AD
Skwish
S
S
Slusarchyk
D A
DA
Allen
G T
GT
Frohlich
B H
BH
Abboa-Offei
B E
BE
Cap
M
M
Waldron
T L
TL
George
R J
RJ
Tesfamariam
B
B
Dickinson
K E
KE
Seymour
A A
AA
Sher
P M
PM
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
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D011412:Propanolamines