p38 MAP kinase inhibitors: Metabolically stabilized piperidine-substituted quinolinones and naphthyridinones

被引：10

作者：

Bao, JM

Hunt, JA

Miao, SW

Rupprecht, KM

Stelmach, JE

Liu, LP

Ruzek, RD

Sinclair, PJ

Pivnichny, JV

Hop, CECA

Kumar, S

Zaller, DM

Shoop, WL

O'Neill, EA

O'Keefe, SJ

Thompson, CM

Cubbon, RM

Wang, RX

Zhang, WX

Thompson, JE

Doherty, JB

机构：

[1] Merck & Co Inc, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck & Co Inc, Dept Drug Metab, Rahway, NJ 07065 USA

[3] Merck & Co Inc, Dept Infammat Rheumatol, Rahway, NJ 07065 USA

[4] Merck & Co Inc, Dept Immunol, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 01期

关键词：

p38; kinase; inflammatory disease; rheumatoid arthritis; quinolinone; naphthyridinone;

D O I：

10.1016/j.bmcl.2005.09.065

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone 4f at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：64 / 68

页数：5

共 8 条

[1] Pyrimidinylimidazole inhibitors of p38: Cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity [J].

Adams, JL ;

Boehm, JC ;

Gallagher, TF ;

Kassis, S ;

Webb, EF ;

Hall, R ;

Sorenson, M ;

Garigipati, R ;

Griswold, DE ;

Lee, JC .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (21) :2867-2870

[2] MAP kinases [J].

Chen, Z ;

Gibson, TB ;

Robinson, F ;

Silvestro, L ;

Pearson, G ;

Xu, BE ;

Wright, A ;

Vanderbilt, C ;

Cobb, MH .

CHEMICAL REVIEWS, 2001, 101 (08) :2449-2476

[3] RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency [J].

Collis, AJ ;

Foster, ML ;

Halley, F ;

Maslen, C ;

McLay, IM ;

Page, KM ;

Redford, EJ ;

Souness, JE ;

Wilsher, NE .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (05) :693-696

[4] p38 inhibitors: Piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones [J].

Hunt, JA ;

Kallashi, F ;

Ruzek, RD ;

Sinclair, PJ ;

Ita, I ;

McCormick, SX ;

Pivnichny, JV ;

Hop, CECA ;

Kumar, S ;

Wang, Z ;

O'Keefe, SJ ;

O'Neill, EA ;

Porter, G ;

Thompson, JE ;

Woods, A ;

Zaller, DM ;

Doherty, JB .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (03) :467-470

[5] A PROTEIN-KINASE INVOLVED IN THE REGULATION OF INFLAMMATORY CYTOKINE BIOSYNTHESIS [J].

LEE, JC ;

LAYDON, JT ;

MCDONNELL, PC ;

GALLAGHER, TF ;

KUMAR, S ;

GREEN, D ;

MCNULTY, D ;

BLUMENTHAL, MJ ;

HEYS, JR ;

LANDVATTER, SW ;

STRICKLER, JE ;

MCLAUGHLIN, MM ;

SIEMENS, IR ;

FISHER, SM ;

LIVI, GP ;

WHITE, JR ;

ADAMS, JL ;

YOUNG, PR .

NATURE, 1994, 372 (6508) :739-746

[6] Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase [J].

Liverton, NJ ;

Butcher, JW ;

Claiborne, CF ;

Claremon, DA ;

Libby, BE ;

Nguyen, KT ;

Pitzenberger, SM ;

Selnick, HG ;

Smith, GR ;

Tebben, A ;

Vacca, JP ;

Varga, SL ;

Agarwal, L ;

Dancheck, K ;

Forsyth, AJ ;

Fletcher, DS ;

Frantz, B ;

Hanlon, WA ;

Harper, CF ;

Hofsess, SJ ;

Kostura, M ;

Lin, J ;

Luell, S ;

O'Neill, EA ;

Orevillo, CJ ;

Pang, M ;

Parsons, J ;

Rolando, A ;

Sahly, Y ;

Visco, DM ;

O'Keefe, SJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (12) :2180-2190

[7] p38 MAP kinase inhibitors.: Part 1:: Design and development of a new class of potent and highly selective inhibitors based on 3,4-dihydropyrido[3,2-d]pyrimidone scaffold [J].

Natarajan, SR ;

Wisnoski, DD ;

Singh, SB ;

Stelmach, JE ;

O'Neill, EA ;

Schwartz, CD ;

Thompson, CM ;

Fitzgerald, CE ;

O'Keefe, SJ ;

Kumar, S ;

Hop, CECA ;

Zaller, DM ;

Schmatz, DM ;

Doherty, JB .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (02) :273-276

[8] Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase [J].

Stelmach, JE ;

Liu, LP ;

Patela, SB ;

Pivnichny, JV ;

Scapin, G ;

Singh, S ;

Hop, CECA ;

Wang, Z ;

Strauss, JR ;

Cameron, PM ;

Nichols, EA ;

O'Keefe, SJ ;

O'Neill, EA ;

Schmatz, DM ;

Schwartz, CD ;

Thompson, CM ;

Zaller, DM ;

Doherty, JB .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (02) :277-280

← 1 →