Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor

被引：28

作者：

Dumas, J

Hatoum-Mokdad, H

Sibley, RN

Smith, RA

Scott, WJ

Khire, U

Lee, W

Wood, J

Wolanin, D

Cooley, J

Bankston, D

Redman, AM

Schoenleber, R

Caringal, Y

Gunn, D

Romero, R

Osterhout, M

Paulsen, H

Housley, TJ

Wilhelm, SM

Pirro, J

Chien, DS

Ranges, GE

Shrikhande, A

Muzsi, A

Bortolon, E

Wakefield, J

Ostravage, CG

Bhargava, A

Chau, T

机构：

[1] Bayer Res Ctr, Dept Chem Res, West Haven, CT 06516 USA

[2] Bayer Res Ctr, Dept Canc & Osteoporosis Res, West Haven, CT 06516 USA

[3] Bayer Res Ctr, Inst Preclin Drug Dev, West Haven, CT 06516 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 12期

关键词：

D O I：

10.1016/S0960-894X(02)00238-X

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis). (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：1559 / 1562

页数：4

共 9 条

[1]

Badger AM, 1996, J PHARMACOL EXP THER, V279, P1453

[2] Discovery of a new class of p38 kinase inhibitors [J].

Dumas, J ;

Sibley, R ;

Riedl, B ;

Monahan, MK ;

Lee, W ;

Lowinger, TB ;

Redman, AM ;

Johnson, JS ;

Kingery-Wood, J ;

Scott, WJ ;

Smith, RA ;

Bobko, M ;

Schoenleber, R ;

Ranges, GE ;

Housley, TJ ;

Bhargava, A ;

Wilhelm, SM ;

Shrikhande, A .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (18) :2047-2050

[3]

DUMAS J, 2001, 222 ACS NAT M CHIC I

[4] 2,4,5-TRIARYLIMIDAZOLE INHIBITORS OF IL-1 BIOSYNTHESIS [J].

GALLAGHER, TF ;

FIERTHOMPSON, SM ;

GARIGIPATI, RS ;

SORENSON, ME ;

SMIETANA, JM ;

LEE, D ;

BENDER, PE ;

LEE, JC ;

LAYDON, JT ;

GRISWOLD, DE ;

CHABOTFLETCHER, MC ;

BRETON, JJ ;

ADAMS, JL .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1995, 5 (11) :1171-1176

[5]

Jackson JR, 1998, J PHARMACOL EXP THER, V284, P687

[6] Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site [J].

Pargellis, C ;

Tong, L ;

Churchill, L ;

Cirillo, PF ;

Gilmore, T ;

Graham, AG ;

Grob, PM ;

Hickey, ER ;

Moss, N ;

Pav, S ;

Regan, J .

NATURE STRUCTURAL BIOLOGY, 2002, 9 (04) :268-272

[7]

RANGES GE, 2000, 220 ACS NAT M WASH D

[8] p38 Kinase inhibitors for the treatment of arthritis and osteoporosis: Thienyl, furyl, and pyrrolyl ureas [J].

Redman, AM ;

Johnson, JS ;

Dally, R ;

Swartz, S ;

Wild, H ;

Paulsen, H ;

Caringal, Y ;

Gunn, D ;

Renick, J ;

Osterhout, M ;

Kingery-Wood, J ;

Smith, RA ;

Lee, W ;

Dumas, J ;

Wilhelm, SM ;

Housley, TJ ;

Bhargava, A ;

Ranges, GE ;

Shrikhande, A ;

Young, D ;

Bombara, M ;

Scott, WJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (01) :9-12

[9] Involvement of p38 MAP kinase in TGF-β-stimulated VEGF synthesis in aortic smooth muscle cells [J].

Yamamoto, T ;

Kozawa, O ;

Tanabe, K ;

Akamatsu, S ;

Matsuno, H ;

Dohi, S ;

Uematsu, T .

JOURNAL OF CELLULAR BIOCHEMISTRY, 2001, 82 (04) :591-598

← 1 →