Development of N-2,4-pyrimidine-N-phenyl-N′-alky ureas as orally active inhibitors of tumor necrosis factor alpha (TNF-α) synthesis.: Part 2

被引：8

作者：

Maier, Jennifer A. ^{[1
]}

Brugel, Todd A. ^{[1
]}

Clark, Michael P. ^{[1
]}

Sabat, Mark ^{[1
]}

Golebiowski, Adam ^{[1
]}

Bookland, Roger G. ^{[1
]}

Laufersweiler, Matthew J. ^{[1
]}

Laughlin, Steven K. ^{[1
]}

VanRens, John C. ^{[1
]}

De, Biswanath ^{[1
]}

Hsieh, Lily C. ^{[1
]}

Brown, Kimberly K. ^{[1
]}

Juergens, Karen ^{[1
]}

Walter, Richard L. ^{[1
]}

Janusz, Michael J. ^{[1
]}

机构：

[1] Procter & Gamble Pharmaceut, Hlth Care Res Ctr, Mason, OH 45040 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 13期

关键词：

cytokine synthesis inhibitors; p38 alpha kinase; urea;

D O I：

10.1016/j.bmcl.2006.03.096

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-a production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38 alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：3514 / 3518

页数：5

共 19 条

[1] Development of N-2,4-pyrimidine-N-phenyl-N′-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-α) synthesis.: Part 1
Brugel, Todd A.
Maier, Jennifer A.
Clark, Michael P.
Sabat, Clark Mark
Goleblowski, Adam
Bookland, Roger G.
Laufersweiler, Matthew J.
Laughlin, Steven K.
VanRens, John C.
De, Biswanath
Hsieh, Lily C.
Mekel, Marlene J.
Janusz, Michael J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (13) : 3510 - 3513
[2] Development of N-2,4-pyrimidine-N-phenyl-N′-phenyl ureas as inhibitors of tumor,necrosis factor alpha (TNF-α) synthesis.: Part 1 (vol 16, pg 3510, 2006)
Brugel, Todd A.
Maier, Jennifer A.
Clark, Michael P.
Sabat, Mark
Goleblowski, Adam
Bookland, Roger G.
Laufersweiler, Matthew J.
Laughlin, Steven K.
VanRens, John C.
De, Biswanath
Hsieh, Lily C.
Mekel, Marlene J.
Janusz, Michael J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (17) : 4700 - 4700
[3] Development of N-4,6-pyrimidine-N-alkyl-N′-phenyl ureas as orally active inhibitors of lymphocyte specific tyrosine kinase
Maier, Jennifer A.
Brugel, Todd A.
Sabat, Mark
Golebiowski, Adam
Laufersweiler, Matthew J.
VanRens, John C.
Hopkins, Corey R.
De, Biswanath
Hsieh, Lily C.
Brown, Kimberly K.
Easwaran, Vijayasurian
Janusz, Michael J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (14) : 3646 - 3650
[4] Development of 1,2,3-triazole based inhibitors of tumor necrosis factor alpha (TNF-α) production.
Van Rens, JC
Clark, MP
Tullis, JS
Natchus, MG
De, B
Hsieh, L
Janusz, MJ
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2003, 225 : U220 - U220
[5] Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors:: Synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N′-{4-[4-quinolyloxy)phenyl}ureas
Kubo, K
Shimizu, T
Ohyama, S
Murooka, H
Iwai, A
Nakamura, K
Hasegawa, K
Kobayashi, Y
Takahashi, N
Takahashi, K
Kato, S
Izawa, T
Isoe, T
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (05) : 1359 - 1366
[6] Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group
Corte, James R.
Fang, Tianan
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Orwat, Michael J.
Rendina, Alan R.
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Harper, Timothy W.
Zheng, Joanna J.
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Seiffert, Dietmar A.
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Quan, Mimi L.
BIOORGANIC & MEDICINAL CHEMISTRY, 2016, 24 (10) : 2257 - 2272
[7] Design, Synthesis, and Antitumor Activity of New N4-Alkyl-N2-Phenyl-Pyrrolo[3,2-d]Pyrimidine-2,4-Diamine Derivatives as CDK6 Inhibitors
Huang, Chuanhui
Wang, Shan
Ma, Weifeng
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY, 2022, 48 (03) : 557 - 564
[8] Design, Synthesis, and Antitumor Activity of New N4-Alkyl-N2-Phenyl-Pyrrolo[3,2-d]Pyrimidine-2,4-Diamine Derivatives as CDK6 Inhibitors
Shan Chuanhui Huang
Weifeng Wang
Russian Journal of Bioorganic Chemistry, 2022, 48 : 557 - 564
[9] Synthesis of [3H], [13C3, 15N], and [14C]SCH 900567: an inhibitor of TNF-α (tumor necrosis factor alpha) converting enzyme (TACE)
Ren, Sumei
Hesk, David
McNamara, Paul
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Borges, Scott
JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 2014, 57 (11): : 632 - 636
[10] Inhibitory effects of menthol, B12N12, B16N16, Al12N12, Al16N16, and their complexes on tumor necrosis factor-alpha (TNF-α) and their potential anti-inflammatory activity: A study using DFT and molecular docking
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Jasim, Saade Abdalkareem
Ortiz, Daniela Tatiana Castaneda
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