Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators

被引：82

作者：

Bemis, Jean E. ^{[1
]}

Vu, Chi B. ^{[1
]}

Xie, Roger ^{[1
]}

Nunes, Joseph J. ^{[1
]}

Ng, Pui Yee ^{[1
]}

Disch, Jeremy S. ^{[1
]}

Milne, Jill C. ^{[1
]}

Carney, David P. ^{[1
]}

Lynch, Amy V. ^{[1
]}

Jin, Lei ^{[1
]}

Smith, Jesse J. ^{[1
]}

Lavu, Siva ^{[1
]}

Iffland, Andre ^{[1
]}

Jirousek, Michael R. ^{[1
]}

Perni, Robert B. ^{[1
]}

机构：

[1] A GSK Co, Sirtris, Cambridge, MA 01239 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 08期

关键词：

Sirtuins; SIRT1; activator; CALORIE RESTRICTION;

D O I：

10.1016/j.bmcl.2008.11.106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol ( 1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol. (C) 2009 Published by Elsevier Ltd.

引用

页码：2350 / 2353

页数：4

共 14 条

[1] Resveratrol improves health and survival of mice on a high-calorie diet [J].

Baur, Joseph A. ;

Pearson, Kevin J. ;

Price, Nathan L. ;

Jamieson, Hamish A. ;

Lerin, Carles ;

Kalra, Avash ;

Prabhu, Vinayakumar V. ;

Allard, Joanne S. ;

Lopez-Lluch, Guillermo ;

Lewis, Kaitlyn ;

Pistell, Paul J. ;

Poosala, Suresh ;

Becker, Kevin G. ;

Boss, Olivier ;

Gwinn, Dana ;

Wang, Mingyi ;

Ramaswamy, Sharan ;

Fishbein, Kenneth W. ;

Spencer, Richard G. ;

Lakatta, Edward G. ;

Le Couteur, David ;

Shaw, Reuben J. ;

Navas, Placido ;

Puigserver, Pere ;

Ingram, Donald K. ;

de Cabo, Rafael ;

Sinclair, David A. .

NATURE, 2006, 444 (7117) :337-342

[2]

BEMIS JE, 2008, 235 NAT M AM CHEM SO

[3] Calorie restriction, SIRT1 and metabolism: Understanding longevity [J].

Bordone, L ;

Guarente, L .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2005, 6 (04) :298-305

[4] SIRT1 transgenic mice show phenotypes resembling calorie restriction [J].

Bordone, Laura ;

Cohen, Dena ;

Robinson, Ashley ;

Motta, Maria Carla ;

van Veen, Ed ;

Czopik, Agnieszka ;

Steele, Andrew D. ;

Crowe, Hayley ;

Marmor, Stephen ;

Luo, Jianyuan ;

Gu, Wei ;

Guarente, Leonard .

AGING CELL, 2007, 6 (06) :759-767

[5] Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase [J].

Cohen, HY ;

Miller, C ;

Bitterman, KJ ;

Wall, NR ;

Hekking, B ;

Kessler, B ;

Howitz, KT ;

Gorospe, M ;

de Cabo, R ;

Sinclair, DA .

SCIENCE, 2004, 305 (5682) :390-392

[6]

Hollander P., 2007, Diabetes Spectrum, V20, P159, DOI 10.2337/diaspect.20.3.159

[7] Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α [J].

Lagouge, Marie ;

Argmann, Carmen ;

Gerhart-Hines, Zachary ;

Meziane, Hamid ;

Lerin, Carles ;

Daussin, Frederic ;

Messadeq, Nadia ;

Milne, Jill ;

Lambert, Philip ;

Elliott, Peter ;

Geny, Bernard ;

Laakso, Markku ;

Puigserver, Pere ;

Auwerx, Johan .

CELL, 2006, 127 (06) :1109-1122

[8] Small molecules that regulate lifespan: evidence for xenohormesis [J].

Lamming, DW ;

Wood, JG ;

Sinclair, DA .

MOLECULAR MICROBIOLOGY, 2004, 53 (04) :1003-1009

[9] Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes [J].

Milne, Jill C. ;

Lambert, Philip D. ;

Schenk, Simon ;

Carney, David P. ;

Smith, Jesse J. ;

Gagne, David J. ;

Jin, Lei ;

Boss, Olivier ;

Perni, Robert B. ;

Vu, Chi B. ;

Bemis, Jean E. ;

Xie, Roger ;

Disch, Jeremy S. ;

Ng, Pui Yee ;

Nunes, Joseph J. ;

Lynch, Amy V. ;

Yang, Hongying ;

Galonek, Heidi ;

Israelian, Kristine ;

Choy, Wendy ;

Iffland, Andre ;

Lavu, Siva ;

Medvedik, Oliver ;

Sinclair, David A. ;

Olefsky, Jerrold M. ;

Jirousek, Michael R. ;

Elliott, Peter J. ;

Westphal, Christoph H. .

NATURE, 2007, 450 (7170) :712-716

[10] SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α [J].

Nemoto, S ;

Fergusson, MM ;

Finkel, T .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (16) :16456-16460

← 1 2 →