Synthesis and evaluation of aryl thioxothiazolidinone inhibitors of ADAMTS-5 (Aggrecanase-2)

被引：48

作者：

Bursavich, Matthew G.

Gilbert, Adam M.

Lombardi, Sabrina

Georgiadis, Katy E.

Reifenberg, Erica

Flannery, Carl R.

Morris, Elisabeth A.

机构：

[1] Wyeth Ayerst Res, Exploratory Med Che,, Chem & Screening Sci, Pearl River, NY 10965 USA

[2] Wyeth Ayerst Res, Womens Hlth & Musculoskeletal Biol, Cambridge, MA 02140 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 05期

关键词：

Aggrecanase; ADAMTS-5; thioxothiazolidinone; metalloprotease inhibitor; zinc chelator;

D O I：

10.1016/j.bmcl.2006.12.027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

5-Benzylidene-2-thioxo-thiazolidin-4-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. The identified compounds show micromolar ADAMTS-5 potency and demonstrate SAR trends for both the aryl group and thioxothiazolidinone zinc chelator. This series of compounds represents steps toward a metalloprotease inhibitor as a disease-modifying osteoarthritis drug. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：1185 / 1188

页数：4

共 13 条

[1] Osteoarthritis [J].

Buckwalter, Joseph A. ;

Martin, James A. .

ADVANCED DRUG DELIVERY REVIEWS, 2006, 58 (02) :150-167

[2] Potent and selective aggrecanase inhibitors containing cyclic P1 substituents [J].

Cherney, RJ ;

Mo, RW ;

Meyer, DT ;

Wang, L ;

Yao, WQ ;

Wasserman, ZR ;

Liu, RQ ;

Covington, MB ;

Tortorella, MD ;

Arner, EC ;

Qian, MX ;

Christ, DD ;

Trzaskos, JM ;

Newton, RC ;

Magolda, RL ;

Decicco, CP .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (07) :1297-1300

[3] 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 [J].

Gilbert, Adam M. ;

Bursavich, Matthew G. ;

Lombardi, Sabrina ;

Georgiadis, Katy E. ;

Reifenberg, Erica ;

Flannery, Carl R. ;

Morris, Elisabeth A. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (05) :1189-1192

[4] Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice [J].

Glasson, SS ;

Askew, R ;

Sheppard, B ;

Carito, BA ;

Blanchet, T ;

Ma, HL ;

Flannery, CR ;

Kanki, K ;

Wang, E ;

Peluso, D ;

Yang, ZY ;

Majumdar, MK ;

Morris, EA .

ARTHRITIS AND RHEUMATISM, 2004, 50 (08) :2547-2558

[5] Synthesis of heterocycle substituted 1-aryl-4-piperidones [J].

Hu, BH ;

Malamas, M ;

Ellingboe, J .

HETEROCYCLES, 2002, 57 (05) :857-870

[6]

Liu R.-Q., 2005, Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents, V4, P251, DOI 10.2174/1568014054065186

[7] The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors [J].

Skiles, JW ;

Gonnella, NC ;

Jeng, AY .

CURRENT MEDICINAL CHEMISTRY, 2004, 11 (22) :2911-2977

[8] ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro [J].

Stanton, H ;

Rogerson, FM ;

East, CJ ;

Golub, SB ;

Lawlor, KE ;

Meeker, CT ;

Little, CB ;

Last, K ;

Farmer, PJ ;

Campbell, IK ;

Fourie, AM ;

Fosang, AJ .

NATURE, 2005, 434 (7033) :648-652

[9] Osteoarthritis - An untreatable disease? [J].

Wieland, HA ;

Michaelis, M ;

Kirschbaum, BJ ;

Rudolphi, KA .

NATURE REVIEWS DRUG DISCOVERY, 2005, 4 (04) :331-344

[10] Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors [J].

Xiang, JS ;

Hu, YH ;

Rush, TS ;

Thomason, JR ;

Ipek, M ;

Sum, PE ;

Abrous, L ;

Sabatini, JJ ;

Georgiadis, K ;

Reifenberg, E ;

Majumdar, M ;

Morris, EA ;

Tam, S .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (02) :311-316

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