Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S

被引：13

作者：

Chatterjee, Arnab K. ^{[1
]}

Liu, Hong ^{[1
]}

Tully, David C. ^{[1
]}

Guo, Jianhua ^{[1
]}

Epple, Robert ^{[1
]}

Russo, Ross ^{[1
]}

Williams, Jennifer ^{[1
]}

Roberts, Michael ^{[1
]}

Tuntland, Tove ^{[1
]}

Chang, Jonathan ^{[1
]}

Gordon, Perry ^{[1
]}

Hollenbeck, Thomas ^{[1
]}

Tumanut, Christine ^{[1
]}

Li, Jun ^{[1
]}

Harris, Jennifer L. ^{[1
]}

机构：

[1] GNF, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 10期

关键词：

cathepsin S; lysosomal proteases; succinamides;

D O I：

10.1016/j.bmcl.2007.02.049

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Peptidic, non-covalent inhibitors of lysosomal cysteine protease cathepsin S (1 and 2) were investigated due to low oral bioavailability, leading to an improved series of peptidomimetic inhibitors. Utilizing phenyl succinamides as the P2 residue increased the oral exposure of this lead series of compounds, while retaining selective inhibition of the cathepsin S isoform. Concurrent investigation of the P1 and P2 subsites resulted in the discovery of several potent and selective inhibitors of cathepsin S with good pharmacokinetic properties due to the elimination of saturated aliphatic P2 residues. (c) 2007 Elsevier Ltd. All rights reserved.

引用

收藏

页码：2899 / 2903

页数：5

相关论文

共 26 条

[1] Arylaminoethyl amides as noncovalent inhibitors of cathepsin S.: Part 2:: Optimization of P1 and N-aryl [J].

Alper, PB ;

Liu, H ;

Chatterjee, AK ;

Nguyen, KT ;

Tully, DC ;

Tumanut, C ;

Li, J ;

Harris, JL ;

Tuntland, T ;

Chang, J ;

Gordon, P ;

Hollenbeck, T ;

Karanewsky, DS .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (06) :1486-1490

[2] New α-substituted succinate-based hydroxamic acids as TNFα convertase inhibitors [J].

Barlaam, B ;

Bird, TG ;

Lambert-van der Brempt, C ;

Campbell, D ;

Foster, SJ ;

Maciewicz, R .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (23) :4890-4908

[3] Cathepsin S controls MHC class II-mediated antigen presentation by epithelial cells in vivo [J].

Beers, C ;

Burich, A ;

Kleijmeer, MJ ;

Griffith, JM ;

Wong, P ;

Rudensky, AY .

JOURNAL OF IMMUNOLOGY, 2005, 174 (03) :1205-1212

[4] Design and synthesis of the cartilage protective agent (CPA, Ro32-3555) [J].

Broadhurst, MJ ;

Brown, PA ;

Lawton, G ;

Ballantyne, N ;

Borkakoti, N ;

Bottomley, KMK ;

Cooper, MI ;

Eatherton, AJ ;

Kilford, IR ;

Malsher, PJ ;

Nixon, JS ;

Lewis, EJ ;

Sutton, BM ;

Johnson, WH .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (17) :2299-2302

[5] Novel in vivo procedure for rapid pharmacokinetic screening of discovery compounds in rats [J].

Cox, KA ;

Dunn-Meynell, K ;

Korfmacher, WA ;

Broske, L ;

Nomeir, AA ;

Lin, CC ;

Cayen, MN ;

Barr, WH .

DRUG DISCOVERY TODAY, 1999, 4 (05) :232-237

[6] Succinimide hydroxamic acids as potent inhibitors of histone deacetylase (HDAC) [J].

Curtin, ML ;

Garland, RB ;

Heyman, HR ;

Frey, RR ;

Michaelides, MR ;

Li, JL ;

Pease, LJ ;

Glaser, KB ;

Marcotte, PA ;

Davidsen, SK .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (20) :2919-2923

[7] Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells [J].

Driessen, C ;

Bryant, RAR ;

Lennon-Duménil, AM ;

Villadangos, JA ;

Bryant, PW ;

Shi, GP ;

Chapman, HA ;

Ploegh, HL .

JOURNAL OF CELL BIOLOGY, 1999, 147 (04) :775-790

[8] THE ASYMMETRIC-SYNTHESIS OF ALPHA-AMINO-ACIDS - ELECTROPHILIC AZIDATION OF CHIRAL IMIDE ENOLATES, A PRACTICAL APPROACH TO THE SYNTHESIS OF (R)-ALPHA-AZIDO AND (S)-ALPHA-AZIDO CARBOXYLIC-ACIDS [J].

EVANS, DA ;

BRITTON, TC ;

ELLMAN, JA ;

DOROW, RL .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1990, 112 (10) :4011-4030

[9]

Hoffmann RW, 2000, ANGEW CHEM INT EDIT, V39, P2054, DOI 10.1002/1521-3773(20000616)39:12<2054::AID-ANIE2054>3.3.CO

[10]

2-Q