Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. Part II.
The left-hand side (LHS) and central part of our first generation biphenyl (FGB) series was modified to improve in vitro and in vivo beta3-AR potency without loss of oral bioavailability. First, in this study, we focused our efforts on replacement of the 3-chlorophenyl moiety in the LHS of FGB analogues with 3-pyridyl ring analogues to adjust the lipophilicity. Second, we investigated the replacement of the central part of this series and discovered that introduction of a methyl group into the alpha-position of the phenethylamine moiety greatly enhanced potency keeping good oral availability. Finally, the replacement of the two carbon linker of the central part with an ethoxy-based linker provided improved potency and PK profiles. As a result of these studies, several analogues (i.e., 9h, 9k, 9l, 10g, 10m, 10p, 10r, 11b, and 11l) were identified that displayed an excellent balance of very higher human beta3-AR potency compared to the FGB compounds, high selectivity, and good pharmacokinetic profiles. Furthermore, these several compounds showed high in vivo efficacy in an overactive bladder (OAB) model. These findings suggest that our selected second generation biphenyl (SGB) series compounds may be attractive new successful therapeutic candidates for the treatment of OAB.
Imanishi
Masashi
M
Chemistry Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Itou
Shinji
S
Washizuka
Kenichi
K
Hamashima
Hitoshi
H
Nakajima
Yutaka
Y
Araki
Takanobu
T
Tomishima
Yasuyo
Y
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
Hattori
Kouji
K
D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists; D000478:Alkylation; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D019817:Benzoic Acid / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D051381:Rats; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D013329:Structure-Activity Relationship
D058667:Adrenergic beta-3 Receptor Agonists; D000588:Amines; D019817:Benzoic Acid; D001713:Biphenyl Compounds; D003432:Cross-Linking Reagents; D022702:Receptors, Adrenergic, beta-3; C010574:biphenyl