Keto-1,3,4-oxadiazoles as cathepsin K inhibitors

被引:60
作者
Palmer, JT
Hirschbein, BL
Cheung, H
McCarter, J
Janc, JW
Yu, ZW
Wesolowski, G
机构
[1] Celera Genom Inc, San Francisco, CA 94080 USA
[2] Merck Res Labs, Dept Bone Biol & Osteoporosis, West Point, PA 19486 USA
基金
美国国家卫生研究院;
关键词
osteoporosis; cathepsin; cysteine protease; inhibitor; ketoheterocycle; reversible; selective; potent;
D O I
10.1016/j.bmcl.2006.03.001
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We have prepared a series of cathepsin K inhibitors bearing the keto-1,3,4-oxadiazole warhead capable of forming a hemithioketal complex with the target enzyme. By modifying binding moieties at the P-1, P-2, and prime side positions of the inhibitors, we have achieved selectivity over cathepsins B, L, and S, and have achieved sub-nanomolar potency against cathepsin K. This series thus represents a promising chemotype that could be used in diseases implicated by imbalances in cathepsin K activity such as osteoporosis. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2909 / 2914
页数:6
相关论文
共 19 条
[1]   Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K [J].
Black, WC ;
Bayly, CI ;
Davis, DE ;
Desmarais, S ;
Falgueyret, JP ;
Léger, S ;
Li, CS ;
Massé, F ;
McKay, DJ ;
Palmer, JT ;
Percival, MD ;
Robichaud, J ;
Tsou, N ;
Zamboni, R .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (21) :4741-4744
[2]   Human cathepsin O-2, a matrix protein-degrading cysteine protease expressed in osteoclasts - Functional expression of human cathepsin O-2 in Spodoptera frugiperda and characterization of the enzyme [J].
Bromme, D ;
Okamoto, K ;
Wang, BB ;
Biroc, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (04) :2126-2132
[3]   Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity [J].
Falgueyret, JP ;
Desmarais, S ;
Oballa, R ;
Black, WC ;
Cromlish, W ;
Khougaz, K ;
Lamontagne, S ;
Massé, F ;
Riendeau, D ;
Toulmond, S ;
Percival, MD .
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (24) :7535-7543
[4]   Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L [J].
Falgueyret, JP ;
Oballa, RM ;
Okamoto, O ;
Wesolowski, G ;
Aubin, Y ;
Rydzewski, RM ;
Prasit, P ;
Riendeau, D ;
Rodan, SB ;
Percival, MD .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (01) :94-104
[5]   Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings [J].
Lipinski, CA ;
Lombardo, F ;
Dominy, BW ;
Feeney, PJ .
ADVANCED DRUG DELIVERY REVIEWS, 1997, 23 (1-3) :3-25
[6]   Potent dipeptidylketone inhibitors of the cysteine protease cathepsin K [J].
Marquis, RW ;
Ru, Y ;
Yamashita, DS ;
Oh, HJ ;
Yen, J ;
Thompson, SK ;
Carr, TJ ;
Levy, MA ;
Tomaszek, TA ;
Ijames, CF ;
Smith, WW ;
Zhao, BG ;
Janson, CA ;
Abdel-Meguid, SS ;
D'Alessio, KJ ;
McQueney, MS ;
Veber, DF .
BIOORGANIC & MEDICINAL CHEMISTRY, 1999, 7 (04) :581-588
[7]   Conformationally constrained 1,3-diamino ketones: A series of potent inhibitors of the cysteine protease cathepsin K [J].
Marquis, RW ;
Yamashita, DS ;
Ru, Y ;
LoCastro, SM ;
Oh, HJ ;
Erhard, KF ;
DesJarlais, RL ;
Head, MS ;
Smith, WW ;
Zhao, BG ;
Janson, CA ;
Abdel-Meguid, SS ;
Tomaszek, TA ;
Levy, MA ;
Veber, DF .
JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (19) :3563-3567
[8]   Azepanone-based inhibitors of human and rat cathepsin K [J].
Marquis, RW ;
Ru, Y ;
LoCastro, SM ;
Zeng, J ;
Yamashita, DS ;
Oh, HJ ;
Erhard, KF ;
Davis, LD ;
Tomaszek, TA ;
Tew, D ;
Salyers, K ;
Proksch, J ;
Ward, K ;
Smith, B ;
Levy, M ;
Cummings, MD ;
Haltiwanger, RC ;
Trescher, G ;
Wang, B ;
Hemling, ME ;
Quinn, CJ ;
Cheng, HY ;
Lin, F ;
Smith, WW ;
Janson, CA ;
Zhao, BG ;
McQueney, MS ;
D'Alessio, K ;
Lee, CP ;
Marzulli, A ;
Dodds, RA ;
Blake, S ;
Hwang, SM ;
James, IE ;
Gress, CJ ;
Bradley, BR ;
Lark, MW ;
Gowen, M ;
Veber, DF .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (09) :1380-1395
[9]   Peptide ketobenzoxazole inhibitors bound to cathepsin K [J].
McGrath, ME ;
Sprengeler, PA ;
Hill, CM ;
Martichonok, V ;
Cheung, H ;
Somoza, JR ;
Palmer, JT ;
Janc, JW .
BIOCHEMISTRY, 2003, 42 (51) :15018-15028
[10]   Novel route to the synthesis of peptides containing 2-amino-1′-hydroxymethyl ketones and their application as cathepsin K inhibitors [J].
Mendonca, RV ;
Venkatraman, S ;
Palmer, JT .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (20) :2887-2891