Discovery of a novel series of benzoic acid derivatives as potent and selective human β3 adrenergic receptor agonists with good oral bioavailability.: 3.: Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety

被引：19

作者：

Imanishi, Masashi ^{[1
]}

Nakajima, Yutaka ^{[1
]}

Tomishima, Yasuyo ^{[1
]}

Hamashima, Hitoshi ^{[1
]}

Washizuka, Kenichi ^{[1
]}

Sakurai, Minoru ^{[1
]}

Matsui, Shigeo ^{[2
]}

Imamura, Emiko ^{[2
]}

Ueshima, Koji ^{[3
]}

Yamamoto, Takao ^{[2
]}

Yamamoto, Nobuhiro ^{[2
]}

Ishikawa, Hirofumi ^{[2
]}

Nakano, Keiko ^{[2
]}

Unami, Naoko ^{[2
]}

Hamada, Kaori ^{[2
]}

Matsumura, Yasuhiro ^{[4
]}

Takamura, Fujiko ^{[4
]}

Hattori, Kouji ^{[1
]}

机构：

[1] Astellas Pharma Inc, Chem Res Labs, Tsukuba, Ibaraki 3058585, Japan

[2] Astellas Pharma Inc, Pharmacol Res Labs, Tsukuba, Ibaraki 3058585, Japan

[3] Astellas Pharma Inc, Appl Pharmacol Res Labs, Tsukuba, Ibaraki 3058585, Japan

[4] Astellas Pharma Inc, Anal & Pharmacokinet Res Labs, Tsukuba, Ibaraki 3058585, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 15期

关键词：

D O I：

10.1021/jm800222k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds (10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC(50) = 0.38 nM) for beta(3), high selectivity over beta(1) and beta(2), and good pharmacokinetic properties in rats, dogs, and monkeys.

引用

页码：4804 / 4822

页数：19

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