Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors

被引：39

作者：

Hammond, Marlys ^{[1
]}

Washburn, David G. ^{[1
]}

Hoang, Tram H. ^{[1
]}

Manns, Sharada ^{[1
]}

Frazee, James S. ^{[1
]}

Nakamura, Hiroko ^{[6
]}

Patterson, Jaclyn R. ^{[1
]}

Trizna, Walter ^{[2
]}

Wu, Charlene ^{[2
]}

Azzarano, Leonard M. ^{[3
]}

Nagilla, Rakesh ^{[3
]}

Nord, Melanie ^{[3
]}

Trejo, Rebecca ^{[3
]}

Head, Martha S. ^{[4
]}

Zhao, Baoguang ^{[4
]}

Smallwood, Angela M. ^{[4
]}

Hightower, Kendra ^{[5
]}

Laping, Nicholas J. ^{[2
]}

Schnackenberg, Christine G. ^{[2
]}

Thompson, Scott K. ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Dept Chem, Metab Pathways Ctr Excellence Drug Discovery, King Of Prussia, PA 19406 USA

[2] GlaxoSmithKline Inc, Dept Biol, Metab Pathways Ctr Excellence Drug Discovery, King Of Prussia, PA 19406 USA

[3] GlaxoSmithKline Inc, Dept Drug Metab & Pharmacokinet, Metab Pathways Ctr Excellence Drug Discovery, King Of Prussia, PA 19406 USA

[4] GlaxoSmithKline Inc, Computat & Struct Chem, Mol Discovery Res, King Of Prussia, PA 19406 USA

[5] GlaxoSmithKline Inc, Screening & Compound Profiling, Mol Discovery Res, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline Inc, Metab Pathways Ctr Excellence Drug Discovery, Discovery Med Chem, Mol Discovery Res, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 15期

关键词：

SGK1; Serum and glucocorticoid-regulated kinase; Kinase inhibitor; Glucuronidation; CELLS; TRANSPORT;

D O I：

10.1016/j.bmcl.2009.05.051

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b] pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：4441 / 4445

页数：5

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