Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides:: novel, potent, selective, and orally bioavailable inhibitors of βII tryptase

被引：31

作者：

Levell, J ^{[1
]}

Astles, P ^{[1
]}

Eastwood, P ^{[1
]}

Cairns, J ^{[1
]}

Houille, O ^{[1
]}

Aldous, S ^{[1
]}

Merriman, G ^{[1
]}

Whiteley, B ^{[1
]}

Pribish, J ^{[1
]}

Czekaj, M ^{[1
]}

Liang, GY ^{[1
]}

Maignan, S ^{[1
]}

Guilloteau, JP ^{[1
]}

Dupuy, A ^{[1
]}

Davidson, J ^{[1
]}

Harrison, T ^{[1
]}

Morley, A ^{[1
]}

Watson, S ^{[1
]}

Fenton, G ^{[1
]}

McCarthy, C ^{[1
]}

Romano, J ^{[1
]}

Mathew, R ^{[1
]}

Engers, D ^{[1
]}

Gardyan, M ^{[1
]}

Sides, K ^{[1
]}

Kwong, J ^{[1
]}

Tsay, J ^{[1
]}

Rebello, S ^{[1
]}

Shen, LD ^{[1
]}

Wang, J ^{[1
]}

Luo, YY ^{[1
]}

Giardino, O ^{[1
]}

Lim, HK ^{[1
]}

Smith, K ^{[1
]}

Pauls, H ^{[1
]}

机构：

[1] Aventis Pharmaceut, Drug Innovat & Approval, Bridgewater, NJ 08807 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 08期

关键词：

tryptase; inhibitors; asthma; X-ray;

D O I：

10.1016/j.bmc.2005.02.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous proinflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human beta II tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：2859 / 2872

页数：14

共 27 条

[1]

Bumagin NA, 1995, ZH ORG KHIM+, V31, P481

[2] Potent selective nonpeptidic inhibitors of human lung tryptase [J].

Burgess, LE ;

Newhouse, BJ ;

Ibrahim, P ;

Rizzi, J ;

Kashem, MA ;

Hartman, A ;

Brandhuber, BJ ;

Wright, CD ;

Thomson, DS ;

Vigers, GPA ;

Koch, K .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (15) :8348-8352

[3]

Bystrov V. F., 1968, ZH OBSHCH KHIM, V38, P1001

[4] Inhibitors of mast cell tryptase beta as therapeutics for the treatment of asthma and inflammatory disorders [J].

Cairns, JA .

PULMONARY PHARMACOLOGY & THERAPEUTICS, 2005, 18 (01) :55-66

[5] Noncardiac chest pain - On the horns of a dilemma [J].

Castell, DO .

JOURNAL OF CLINICAL GASTROENTEROLOGY, 2002, 34 (01) :3-3

[6] Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand [J].

Choi-Sledeski, YM ;

Kearney, R ;

Poli, G ;

Pauls, H ;

Gardner, C ;

Gong, Y ;

Becker, M ;

Davis, R ;

Spada, A ;

Liang, G ;

Chu, V ;

Brown, K ;

Collussi, D ;

Leadley, R ;

Rebello, S ;

Moxey, P ;

Morgan, S ;

Bentley, R ;

Kasiewski, C ;

Maignan, S ;

Guilloteau, JP ;

Mikol, V .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (05) :681-684

[7] Aminoisoquinolines: Design and synthesis of an orally active benzamidine isostere for the inhibition of factor Xa. [J].

Choi-Sledeski, YM ;

Becker, MR ;

Green, DM ;

Davis, R ;

Ewing, WR ;

Mason, HJ ;

Ly, C ;

Spada, A ;

Liang, G ;

Cheney, D ;

Barton, J ;

Chu, V ;

Brown, K ;

Colussi, D ;

Bentley, R ;

Leadley, R ;

Dunwiddie, C ;

Pauls, HW .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (17) :2539-2544

[8] Comparison of in vitro preparations for semi-quantitative prediction of in vivo drug metabolism [J].

De Graaf, IAM ;

Van Meijeren, CE ;

Pektas, F ;

Koster, HJ .

DRUG METABOLISM AND DISPOSITION, 2002, 30 (10) :1129-1136

[9]

EABORN C, 1967, J CHEM SOC C, V15, P1364

[10] A versatile synthesis of 4-aryl tetrahydropyridines via palladium mediated Suzuki cross-coupling with cyclic vinyl boronates [J].

Eastwood, PR .

TETRAHEDRON LETTERS, 2000, 41 (19) :3705-3708

← 1 2 3 →