Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6.
As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.
Hattori
Kouji
K
Chemistry Research Laboratories, Astellas Pharma Inc, Tsukuba-shi, Ibaraki 305-8585, Japan. kouji.hattori@jp.astellas.com
Orita
Masaya
M
Toda
Susumu
S
Imanishi
Masashi
M
Itou
Shinji
S
Nakajima
Yutaka
Y
Tanabe
Daisuke
D
Washizuka
Kenichi
K
Araki
Takanobu
T
Sakurai
Minoru
M
Matsui
Shigeo
S
Imamura
Emiko
E
Ueshima
Koji
K
Yamamoto
Takao
T
Yamamoto
Nobuhiro
N
Ishikawa
Hirofumi
H
Nakano
Keiko
K
Unami
Naoko
N
Hamada
Kaori
K
Matsumura
Yasuhiro
Y
Takamura
Fujiko
F
D000322:Adrenergic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D008956:Models, Chemical; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D000322:Adrenergic Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides