Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1′, P1, and/or P3 substitutions

被引：30

作者：

Barrett, DG

Catalano, JG ^{[1
]}

Deaton, DN

Hassell, AM

Long, ST

Miller, AB

Miller, LR

Shewchuk, LM

Wells-Knecht, KJ

Willard, DH

Wright, LL

机构：

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

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

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

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

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

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 19期

关键词：

cathepsin K; ketoamide; cysteine protease inhibitor;

D O I：

10.1016/j.bmcl.2004.07.031

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P-2 substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P-3, p(1), and P-1' moieties afforded orally bioavailable inhibitors. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：4897 / 4902

页数：6

共 17 条

[1] Orally bioavailable small molecule ketoamide-based inhibitors of cathepsin K [J].

Barrett, DG ;

Catalano, JG ;

Deaton, DN ;

Long, ST ;

Miller, LR ;

Tavares, FX ;

Wells-Knecht, KJ ;

Wright, LL ;

Zhou, HQQ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (10) :2543-2546

[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] 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] 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

[6]

Einhorn Thomas A., 1996, P3

[7]

FINKELSHTEIN ES, 1980, NEFTEKHIMIYA, V20, P75

[8] MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening [J].

Irvine, JD ;

Takahashi, L ;

Lockhart, K ;

Cheong, J ;

Tolan, JW ;

Selick, HE ;

Grove, JR .

JOURNAL OF PHARMACEUTICAL SCIENCES, 1999, 88 (01) :28-33

[9]

LAMBERT MH, 1997, PRACTICAL APPL COMPU, P243

[10] 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

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