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.
Chemistry Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Masashi
M
Imanishi
Shinji
S
Itou
Kenichi
K
Washizuka
Hitoshi
H
Hamashima
Yutaka
Y
Nakajima
Takanobu
T
Araki
Yasuyo
Y
Tomishima
Minoru
M
Sakurai
Shigeo
S
Matsui
Emiko
E
Imamura
Koji
K
Ueshima
Takao
T
Yamamoto
Nobuhiro
N
Yamamoto
Hirofumi
H
Ishikawa
Keiko
K
Nakano
Naoko
N
Unami
Kaori
K
Hamada
Yasuhiro
Y
Matsumura
Fujiko
F
Takamura
Kouji
K
Hattori
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