Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: Heterocyclic P3

被引:58
作者
Tully, DC [1 ]
Liu, H [1 ]
Alper, PB [1 ]
Chatterjee, AK [1 ]
Epple, R [1 ]
Roberts, MJ [1 ]
Williams, JA [1 ]
Nguyen, KT [1 ]
Woodmansee, DH [1 ]
Tumanut, C [1 ]
Li, J [1 ]
Spraggon, G [1 ]
Chang, J [1 ]
Tuntland, T [1 ]
Harris, JL [1 ]
Karanewsky, DS [1 ]
机构
[1] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA
关键词
cathepsin S; cathepsin; cysteine protease inhibitor; noncovalent inhibitor; peptidomimetics;
D O I
10.1016/j.bmcl.2005.12.095
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of N-alpha-2-benzoxazolyl-alpha-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported. (C) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1975 / 1980
页数:6
相关论文
共 17 条
[1]  
ALPER PB, 2006, IN PRESS BIOORG MED
[2]   Arylaminoethyl amides as inhibitors of the cysteine protease cathepsin K -: Investigating P1′ substituents [J].
Altmann, E ;
Green, J ;
Tintelnot-Blomley, M .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (12) :1997-2001
[3]   Arylaminoethyl amides as novel non-covalent cathepsin K inhibitors [J].
Altmann, E ;
Renaud, J ;
Green, J ;
Farley, D ;
Cutting, B ;
Jahnke, W .
JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (12) :2352-2354
[4]   N-arylaminonitriles as bioavailable peptidomimetic inhibitors of cathepsin B [J].
Greenspan, PD ;
Clark, KL ;
Cowen, SD ;
McQuire, LW ;
Tommasi, RA ;
Farley, DL ;
Quadros, E ;
Coppa, DE ;
Du, ZM ;
Fang, Z ;
Zhou, HH ;
Doughty, J ;
Toscano, KT ;
Wigg, AM ;
Zhou, SY .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (22) :4121-4124
[5]   3-[1-(2-BENZOXAZOLYL)HYDRAZINO]PROPANENITRILE DERIVATIVES - INHIBITORS OF IMMUNE-COMPLEX INDUCED INFLAMMATION [J].
HAVIV, F ;
RATAJCZYK, JD ;
DENET, RW ;
KERDESKY, FA ;
WALTERS, RL ;
SCHMIDT, SP ;
HOLMS, JH ;
YOUNG, PR ;
CARTER, GW .
JOURNAL OF MEDICINAL CHEMISTRY, 1988, 31 (09) :1719-1728
[6]   Cathepsin S inhibitors [J].
Leroy, V ;
Thurairatnam, S .
EXPERT OPINION ON THERAPEUTIC PATENTS, 2004, 14 (03) :301-311
[7]   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
[8]   Cysteine protease cathepsin S as a key step in antigen presentation [J].
Liu, WM ;
Spero, DM .
DRUG NEWS & PERSPECTIVES, 2004, 17 (06) :357-363
[9]   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
[10]   The role of metabolic activation in drug-induced hepatotoxicity [J].
Park, BK ;
Kitteringham, NR ;
Maggs, JL ;
Pirmohamed, M ;
Williams, DP .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2005, 45 :177-202