Beta 3 agonists. Part 1: evolution from inception to BMS-194449.
Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)
Washburn
W N
WN
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. william.washburn@bms.com
Sher
P M
PM
Poss
K M
KM
Girotra
R N
RN
McCann
P J
PJ
Gavai
A V
AV
Mikkilineni
A B
AB
Mathur
A
A
Cheng
P
P
Dejneka
T C
TC
Sun
C Q
CQ
Wang
T C
TC
Harper
T W
TW
Russell
A D
AD
Slusarchyk
D A
DA
Skwish
S
S
Allen
G T
GT
Hillyer
D E
DE
Frohlich
B H
BH
Abboa-Offei
B E
BE
Cap
M
M
Waldron
T L
TL
George
R J
RJ
Tesfamariam
B
B
Ciosek
C P
CP
Ryono
D
D
Young
D A
DA
Dickinson
K E
KE
Seymour
A A
AA
Arbeeny
C M
CM
Gregg
R E
RE
D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000737:chemistry* / Q000494:pharmacology*; D000813:Anilides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D019856:Ethanolamine / Q000737:chemistry* / Q000494:pharmacology*; D004983:Ethanolamines; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000813:Anilides; D004983:Ethanolamines; D019856:Ethanolamine; C448379:BMS-194449