Orally bioavailable small molecule ketoamide-based inhibitors of cathepsin K

被引：15

作者：

Barrett, DG

Catalano, JG

Deaton, DN ^{[1
]}

Long, ST

Miller, LR

Tavares, FX

Wells-Knecht, KJ

Wright, LL

Zhou, HQQ

机构：

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

[2] GlaxoSmithKline, Discovery Res Biol, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline, Dept Res Bioanal & Drug Metab, Res Triangle Pk, NC 27709 USA

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

[5] GlaxoSmithKline, Dept World Wide Phys Properties, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 10期

关键词：

cathepsin K; ketoamide; cysteine protease inhibitors;

D O I：

10.1016/j.bmcl.2004.02.085

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P-1 and P-1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors. (C) 2004 Elsevier Ltd. All rights reserved.

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收藏

页码：2543 / 2546

页数：4

相关论文

共 24 条

[1] Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors.: Use of L-mannaric acid as a peptidomimetic scaffold [J].

Alterman, M ;

Björsne, M ;

Mühlman, A ;

Classon, B ;

Kvarnström, I ;

Danielson, H ;

Markgren, PO ;

Nillroth, U ;

Unge, T ;

Hallberg, A ;

Samuelsson, B .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (20) :3782-3792

[2] Intramolecular opening of β-lactams with amines as a strategy toward enzymatically or photochemically triggered activation of lactenediyne prodrugs [J].

Banfi, L ;

Guanti, G ;

Rasparini, M .

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2003, 2003 (07) :1319-1336

[3] Design of small molecule ketoamide-based inhibitors of cathepsin K [J].

Catalano, JG ;

Deaton, DN ;

Long, ST ;

McFadyen, RB ;

Miller, LR ;

Payne, JA ;

Wells-Knecht, KJ ;

Wright, LL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (03) :719-722

[4] 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

[5]

CATALANO JG, 2003, Patent No. 03062192

[6] Differential effects of glucocorticoids on bone resorption in neonatal mouse calvariae stimulated by peptide and steroid-like hormones [J].

Conaway, HH ;

Grigorie, D ;

Lerner, UH .

JOURNAL OF ENDOCRINOLOGY, 1997, 155 (03) :513-521

[7] A GENERAL-METHOD FOR THE SYNTHESIS OF TETRAMIC ACID-DERIVATIVES [J].

DESHONG, P ;

CIPOLLINA, JA ;

LOWMASTER, NK .

JOURNAL OF ORGANIC CHEMISTRY, 1988, 53 (07) :1356-1364

[8] Dissolution testing as a prognostic tool for oral drug absorption: Immediate release dosage forms [J].

Dressman, JB ;

Amidon, GL ;

Reppas, C ;

Shah, VP .

PHARMACEUTICAL RESEARCH, 1998, 15 (01) :11-22

[9]

Einhorn Thomas A., 1996, P3

[10] CORTISOL MODULATION OF OSTEOBLAST METABOLIC-ACTIVITY IN CULTURED NEONATAL RAT BONE [J].

HAHN, TJ ;

WESTBROOK, SL ;

HALSTEAD, LR .

ENDOCRINOLOGY, 1984, 114 (05) :1864-1870