Discovery of a Novel Series of Biphenyl Benzoic Acid Derivatives as Highly Potent and Selective Human β3 Adrenergic Receptor Agonists with Good Oral Bioavailability. Part II

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• 作者：Masashi Imanishi ; Shinji Itou ; Kenichi Washizuka ; Hitoshi Hamashima ; Yutaka Nakajima ; Takanobu Araki ; Yasuyo Tomishima ; Minoru Sakurai ; Shigeo Matsui ; Emiko Imamura ; Koji Ueshima ; Takao Yamamoto ; Nobu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：July 10, 2008
• 年：2008
• 卷：51
• 期：13
• 页码：4002 - 4020
• 全文大小：336K
• 年卷期：v.51,no.13(July 10, 2008)
• ISSN：1520-4804

文摘

The left-hand side (LHS) and central part of our first generation biphenyl (FGB) series was modified to improve in vitro and in vivo β3-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 α-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 β3-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.