Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers

被引:30
作者
Tully, David C. [1 ]
Liu, Hong [1 ]
Chatterjee, Arnab K. [1 ]
Alper, Phil B. [1 ]
Epple, Robert [1 ]
Williams, Jennifer A. [1 ]
Roberts, Michael J. [1 ]
Woodmansee, David H. [1 ]
Masick, Brian T. [1 ]
Tumanut, Christine [1 ]
Li, Jun [1 ]
Spraggon, Glen [1 ]
Hornsby, Michael [1 ]
Chang, Jonathan [1 ]
Tuntland, Tove [1 ]
Hollenbeck, Thomas [1 ]
Gordon, Perry [1 ]
Harris, Jennifer L. [1 ]
Karanewsky, Donald S. [1 ]
机构
[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA
关键词
cathepsin S; cysteine protease inhibitor; noncovalent inhibitor; peptidomimetic; X-ray structure;
D O I
10.1016/j.bmcl.2006.07.033
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.
引用
收藏
页码:5112 / 5117
页数:6
相关论文
共 18 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]   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
[3]   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
[4]   Cathepsin S inhibitors [J].
Leroy, V ;
Thurairatnam, S .
EXPERT OPINION ON THERAPEUTIC PATENTS, 2004, 14 (03) :301-311
[5]   Design and synthesis of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part I [J].
Liu, H ;
Tully, DC ;
Epple, R ;
Bursulaya, B ;
Li, J ;
Harris, JL ;
Williams, JA ;
Russo, R ;
Tumanut, C ;
Roberts, MJ ;
Alper, PB ;
He, Y ;
Karanewsky, DS .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (22) :4979-4984
[6]   Azepanone-based inhibitors of human cathepsin L [J].
Marquis, RW ;
James, I ;
Zeng, J ;
Trout, REL ;
Thompson, S ;
Rahman, A ;
Yamashita, DS ;
Xie, R ;
Ru, Y ;
Gress, CJ ;
Blake, S ;
Lark, MA ;
Hwang, SM ;
Tomaszek, T ;
Offen, P ;
Head, MS ;
Cummings, MD ;
Veber, DF .
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (22) :6870-6878
[7]   Crystal structure of human cathepsin S [J].
McGrath, ME ;
Palmer, JT ;
Brömme, D ;
Somoza, JR .
PROTEIN SCIENCE, 1998, 7 (06) :1294-1302
[8]   Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in cathepsin S null mice [J].
Nakagawa, TY ;
Brissette, WH ;
Lira, PD ;
Griffiths, RJ ;
Petrushova, N ;
Stock, J ;
McNeish, JD ;
Eastman, SE ;
Howard, ED ;
Clarke, SRM ;
Rosloniec, EF ;
Elliott, EA ;
Rudensky, AY .
IMMUNITY, 1999, 10 (02) :207-217
[9]   The role of lysosomal proteinases in MHC class II-mediated antigen processing and presentation [J].
Nakagawa, TY ;
Rudensky, AY .
IMMUNOLOGICAL REVIEWS, 1999, 172 :121-129
[10]   Specificity determinants of human cathepsin S revealed by crystal structures of complexes [J].
Pauly, TA ;
Sulea, T ;
Ammirati, M ;
Sivaraman, J ;
Danley, DE ;
Griffor, MC ;
Kamath, AV ;
Wang, LK ;
Laird, ER ;
Seddon, AP ;
Ménard, R ;
Cygler, M ;
Rath, VL .
BIOCHEMISTRY, 2003, 42 (11) :3203-3213