Novel and potent cyclic cyanamide-based cathepsin K inhibitors

被引：36

作者：

Deaton, DN ^{[1
]}

Hassell, AM

McFadyen, RB

Miller, AB

Miller, LR

Shewchuk, LM

Tavares, FX

Willard, DH

Wright, LL

机构：

[1] GlaxoSmithKline, Dept Med Chem, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline, Discovery Res Computat Analy & Struct Sci, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline, Dept Mol Pharmacol, Res Triangle Pk, NC 27709 USA

[4] GlaxoSmithKline, Dept Gene Express & Prot Purificat, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline, Discovery Res biol, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 07期

关键词：

cathepsin K; cyanamide; cysteine protease inhibitor; warhead;

D O I：

10.1016/j.bmcl.2005.02.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from a PDE IV inhibitor hit derived from high throughput screening of the compound collection, a key pyrrolidine cyanamide pharmacophore was identified. Modifications of the pyrrolidine ring produced enhancements in cathepsin K inhibition. An X-ray co-crystal structure of a cyanamide with cathepsin K confirmed the mode of inhibition. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：1815 / 1819

页数：5

共 16 条

[1]

BARRETT DG, 2002, 3 INT C CYST PROT TH, P95

[2] Exploration of the P2-P3SAR of aldehyde cathepsin K inhibitors [J].

Boros, EE ;

Deaton, DN ;

Hassell, AM ;

McFadyen, RB ;

Miller, AB ;

Miller, LR ;

Paulick, MG ;

Shewchuk, LM ;

Thompson, JB ;

Willard, DH ;

Wright, LL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (13) :3425-3429

[3] Exploration of the P1SAR of aldehyde cathepsin K inhibitors [J].

Catalano, JG ;

Deaton, DN ;

Furfine, ES ;

Hassell, AM ;

McFadyen, RB ;

Miller, AB ;

Miller, LR ;

Shewchuk, LM ;

Willard, DH ;

Wright, LL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (01) :275-278

[4]

Deaton DN, 2004, PROGR MED CHEM, V42, P245, DOI 10.1016/S0079-6468(04)42006-2

[5] POLYPEPTIDES .13. PREPARATION OF ALPHA-AZA-AMINO-ACID (CARBAZIC ACID) DERIVATIVES AND INTERMEDIATES FOR PREPARATION OF ALPHA-AZA-PEPTIDES [J].

DUTTA, AS ;

MORLEY, JS .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1975, (17) :1712-1720

[6]

EGBERTSON M, 1989, J ORG CHEM, V54, P1

[7]

Einhorn Thomas A., 1996, P3

[8] 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

[9] PHOSPHODIESTERASE TYPE-IV INHIBITION - STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1,3-DISUBSTITUTED PYRROLIDINES [J].

FELDMAN, PL ;

BRACKEEN, MF ;

COWAN, DJ ;

MARRON, BE ;

SCHOENEN, FJ ;

STAFFORD, JA ;

SUH, EM ;

DOMANICO, PL ;

ROSE, D ;

LEESNITZER, MA ;

BRAWLEY, ES ;

STRICKLAND, AB ;

VERGHESE, MW ;

CONNOLLY, KM ;

BATEMANFITE, R ;

NOEL, LS ;

SEKUT, L ;

STIMPSON, SA .

JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (09) :1505-1510

[10] Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency [J].

Gelb, BD ;

Shi, GP ;

Chapman, HA ;

Desnick, RJ .

SCIENCE, 1996, 273 (5279) :1236-1238

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