The discovery and initial optimisation of pyrrole-2-carboxamides as inhibitors of p38α MAP kinase

被引：14

作者：

Down, Kenneth ^{[1
]}

Bamborough, Paul ^{[2
]}

Alder, Catherine ^{[1
]}

Campbell, Amanda ^{[1
]}

Christopher, John A. ^{[2
]}

Gerelle, Maria ^{[1
]}

Ludbrook, Steve ^{[2
]}

Mallett, Dave ^{[1
]}

Mellor, Geoff ^{[2
]}

Miller, David D. ^{[1
]}

Pearson, Rosannah ^{[2
]}

Ray, Keith ^{[1
]}

Solanke, Yemisi ^{[1
]}

Somers, Don ^{[2
]}

机构：

[1] GlaxoSmithKline R&D, Resp Ctr Excellence Drug Discovery, Med Res Ctr, Stevenage SG1 2NY, Herts, England

[2] GlaxoSmithKline R&D, Mol Discovery Res, Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 13期

关键词：

p38 alpha MAP kinase; DOUBLE-BLIND; P38; EFFICACY; SAFETY;

D O I：

10.1016/j.bmcl.2010.05.011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel pyrrole-2-carboxamide series of p38 alpha inhibitors, discovered through the application of virtual screening, is presented. Following evaluation of activity, selectivity and developability properties of commercially available analogues, a synthesis program enabled rapid assessment of the series' suitability for further lead optimisation studies. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：3936 / 3940

页数：5

共 17 条

[1] Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity [J].

Angell, Richard ;

Aston, Nicola M. ;

Bamborough, Paul ;

Buckton, Jacky B. ;

Cockerill, Stuart ;

deBoeck, Suzanne J. ;

Edwards, Chris D. ;

Holmes, Duncan S. ;

Jones, Katherine L. ;

Laine, Dramane I. ;

Patel, Shila ;

Smee, Penny A. ;

Smith, Kathryn J. ;

Somers, Don O. ;

Walker, Ann L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (15) :4428-4432

[2] Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes [J].

Angell, Richard M. ;

Angell, Tony D. ;

Bamborough, Paul ;

Bamford, Mark J. ;

Chung, Chun-wa ;

Cockerill, Stuart G. ;

Flack, Stephen S. ;

Jones, Katherine L. ;

Laine, Dramane I. ;

Longstaff, Timothy ;

Ludbrook, Steve ;

Pearson, Rosannah ;

Smith, Kathryn J. ;

Smee, Penny A. ;

Somers, Don O. ;

Walker, Ann L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (15) :4433-4437

[3] Biphenyl amide p38 kinase inhibitors 2: Optimisation and SAR [J].

Angell, Richard M. ;

Angell, Tony D. ;

Bamborough, Paul ;

Brown, David ;

Brown, Murray ;

Buckton, Jacky B. ;

Cockerill, Stuart G. ;

Edwards, Chris D. ;

Jones, Katherine L. ;

Longstaff, Tim ;

Smee, Penny A. ;

Smith, Kathryn J. ;

Somers, Don O. ;

Walker, Ann L. ;

Willson, Malcolm .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (01) :324-328

[4] Biphenyl amide p38 kinase inhibitors 1: Discovery and binding mode [J].

Angell, Richard M. ;

Bamborough, Paul ;

Cleasby, Anne ;

Cockerill, Stuart G. ;

Jones, Katherine L. ;

Mooney, Christopher J. ;

Somers, Donald O. ;

Walker, Ann L. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (01) :318-323

[5] Discovery of 6-Aryl-7-alkoxyisoquinoline Inhibitors of IκB Kinase-β (IKK-β) [J].

Christopher, John A. ;

Bamborough, Paul ;

Alder, Catherine ;

Campbell, Amanda ;

Cutler, Geoffrey J. ;

Down, Kenneth ;

Hamadi, Ahmed M. ;

Jolly, Adrian M. ;

Kerns, Jeffrey K. ;

Lucas, Fiona S. ;

Mellor, Geoffrey W. ;

Miller, David D. ;

Morse, Mary A. ;

Pancholi, Kiritkant D. ;

Rumsey, William ;

Solanke, Yemisi E. ;

Williamson, Rick .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (09) :3098-3102

[6] Evaluation of the Efficacy and Safety of Pamapimod, a p38 MAP Kinase Inhibitor, in a Double-Blind, Methotrexate-Controlled Study of Patients With Active Rheumatoid Arthritis [J].

Cohen, Stanley B. ;

Cheng, Tien-Tsai ;

Chindalore, Vishala ;

Damjanov, Nemanja ;

Burgos-Vargas, Ruben ;

DeLora, Patricia ;

Zimany, Kathleen ;

Travers, Helen ;

Caulfield, John P. .

ARTHRITIS AND RHEUMATISM, 2009, 60 (02) :335-344

[7] Efficacy, Pharmacodynamics, and Safety of VX-702, a Novel p38 MAPK Inhibitor, in Rheumatoid Arthritis Results of Two Randomized, Double-Blind, Placebo-Controlled Clinical Studies [J].

Damjanov, Nemanja ;

Kauffman, Robert S. ;

Spencer-Green, George T. .

ARTHRITIS AND RHEUMATISM, 2009, 60 (05) :1232-1241

[8] A small molecule-kinase interaction map for clinical kinase inhibitors [J].

Fabian, MA ;

Biggs, WH ;

Treiber, DK ;

Atteridge, CE ;

Azimioara, MD ;

Benedetti, MG ;

Carter, TA ;

Ciceri, P ;

Edeen, PT ;

Floyd, M ;

Ford, JM ;

Galvin, M ;

Gerlach, JL ;

Grotzfeld, RM ;

Herrgard, S ;

Insko, DE ;

Insko, MA ;

Lai, AG ;

Lélias, JM ;

Mehta, SA ;

Milanov, ZV ;

Velasco, AM ;

Wodicka, LM ;

Patel, HK ;

Zarrinkar, PP ;

Lockhart, DJ .

NATURE BIOTECHNOLOGY, 2005, 23 (03) :329-336

[9] Inhibition of p38: Has the Fat Lady Sung [J].

Genovese, Mark C. .

ARTHRITIS AND RHEUMATISM, 2009, 60 (02) :317-320

[10]

Goldstein DM, 2010, J MED CHEM, V53, P2345, DOI [10.1021/acs.jmedchem.8b00124, 10.1021/jm9012906]

← 1 2 →