Investigation of ketone warheads as alternatives to the nitrile for preparation of potent and selective cathepsin K inhibitors

被引：23

作者：

Boyd, Michael J. ^{[1
]}

Crane, Sheldon N. ^{[1
]}

Robichaud, Joel ^{[1
]}

Scheigetz, John ^{[1
]}

Black, W. Cameron ^{[1
]}

Chauret, Nathalie ^{[1
]}

Wang, Qingping ^{[1
]}

Masse, Frederic ^{[1
]}

Oballa, Renata M. ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Pointe Claire, PQ H9R 4P8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 03期

关键词：

Cathepsin K; Ketone; Odanacatib; DESIGN;

D O I：

10.1016/j.bmcl.2008.12.053

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect on metabolism and pharmacokinetics. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：675 / 679

页数：5

共 30 条

[1] Dipeptide nitrile inhibitors of cathepsin K [J].

Altmann, E ;

Aichholz, R ;

Betschart, C ;

Buhl, T ;

Green, J ;

Lattmann, R ;

Missbach, M .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (09) :2549-2554

[2] Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis [J].

Asagiri, Masataka ;

Hirai, Toshitake ;

Kunigami, Toshihiro ;

Kamano, Shunya ;

Gober, Hans-Juergen ;

Okamoto, Kazuo ;

Nishikawa, Keizo ;

Latz, Eicke ;

Golenbock, Douglas T. ;

Aoki, Kazuhiro ;

Ohya, Keiichi ;

Imai, Yuuki ;

Morishita, Yasuyuki ;

Miyazono, Kohei ;

Kato, Shigeaki ;

Saftig, Paul ;

Takayanagi, Hiroshi .

SCIENCE, 2008, 319 (5863) :624-627

[3] Novel, potent P2-P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors [J].

Barrett, DG ;

Catalano, JG ;

Deaton, DN ;

Hassell, AM ;

Long, ST ;

Miller, AB ;

Miller, LR ;

Ray, JA ;

Samano, V ;

Shewchuk, LM ;

Wells-Knecht, KJ ;

Willard, DH ;

Wright, LL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (06) :1735-1739

[4]

BAYLY CI, 2003, Patent No. 2003075836

[5] 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

[6] 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

[7] Cathepsin K inhibitors, 2000-2004 [J].

Cai, JQ ;

Jamieson, C ;

Moir, J ;

Rankovic, Z .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2005, 15 (01) :33-48

[8] β-substituted cyclohexanecarboxamide:: A nonpeptidic framework for the design of potent inhibitors of cathepsin K [J].

Crane, SN ;

Black, WC ;

Palmer, JT ;

Davis, DE ;

Setti, E ;

Robichaud, J ;

Paquet, J ;

Oballa, RM ;

Bayly, CI ;

McKay, DJ ;

Somoza, JR ;

Chauret, N ;

Seto, C ;

Scheigetz, J ;

Wesolowski, G ;

Massé, F ;

Desmarais, S ;

Ouellet, M .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (03) :1066-1079

[9] Design of cathepsin K inhibitors for osteoporosis [J].

Deaton, DN ;

Tavares, FX .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (16) :1639-1675

[10] Diastereoselective synthesis, activity and chiral stability of cyclic alkoxyketone inhibitors of cathepsin K [J].

Fenwick, AE ;

Gribble, AD ;

Ife, RJ ;

Stevens, N ;

Witherington, J .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (02) :199-202

← 1 2 3 →