Discovery of a novel pyrazole series of group X secreted phospholipase A2 inhibitor (sPLA2X) via fragment based virtual screening

被引：11

作者：

Chen, Hongming ^{[1
]}

Knerr, Laurent ^{[1
]}

Akerud, Tomas ^{[3
]}

Hallberg, Kenth ^{[3
]}

Oster, Linda ^{[3
]}

Rohman, Mattias ^{[4
]}

Osterlund, Krister ^{[2
]}

Beisel, Hans-Georg ^{[2
]}

Olsson, Thomas ^{[2
]}

Brengdhal, Johan ^{[2
]}

Sandmark, Jenny ^{[3
]}

Bodin, Cristian ^{[3
]}

机构：

[1] AstraZeneca R&D, Discovery Sci, Chem Innovat Ctr, SE-43183 Molndal, Sweden

[2] AstraZeneca R&D, CVMD Innovat Med, SE-43183 Molndal, Sweden

[3] AstraZeneca R&D, Discovery Sci, Struct & Biophys, SE-43183 Molndal, Sweden

[4] AstraZeneca R&D, Discovery Sci, Reagents & Assay Dev, SE-43183 Molndal, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 22期

关键词：

sPLA(2)X inhibitor; FBLG; Pharmacophore model; Virtual screening; INDOLE INHIBITORS; A(2); ATHEROSCLEROSIS;

D O I：

10.1016/j.bmcl.2014.09.058

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of potent novel pyrazole containing group X secreted phospholipase A2 inhibitors via structure based virtual screening is reported. Docking was applied on a large set of in-house fragment collection and pharmacophore feature matching was used to filter docking poses. The selected virtual screening hits was run in NMR screening, a potent pyrazole containing fragment hit was identified and confirmed by its complex X-ray structure and the following biochemical assay result. Expansion on the fragment hit has led to further improvement of potency while maintaining high ligand efficiency, thus supporting the further development of this chemical series. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：5251 / 5255

页数：5

共 20 条

[1] Group X Secreted Phospholipase A2 Limits the Development of Atherosclerosis in LDL Receptor-Null Mice [J].

Ait-Oufella, Hafid ;

Herbin, Olivier ;

Lahoute, Charlotte ;

Coatrieux, Christelle ;

Loyer, Xavier ;

Joffre, Jeremie ;

Laurans, Ludivine ;

Ramkhelawon, Bhama ;

Blanc-Brude, Olivier ;

Karabina, Sonia ;

Girard, Christophe A. ;

Payre, Christine ;

Yamamoto, Kei ;

Binder, Christoph J. ;

Murakami, Makoto ;

Tedgui, Alain ;

Lambeau, Gerard ;

Mallat, Ziad .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2013, 33 (03) :466-+

[2]

[Anonymous], 2007, SZYBK VERS 1 2 2

[3]

[Anonymous], 2007, GLID VERS 4 5

[4]

[Anonymous], 2007, CLOGP VERS 4 3

[5] Fragment-based discovery of JAK-2 inhibitors [J].

Antonysamy, Stephen ;

Hirst, Gavin ;

Park, Frances ;

Sprengeler, Paul ;

Stappenbeck, Frank ;

Steensma, Ruo ;

Wilson, Mark ;

Wong, Melissa .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (01) :279-282

[6] Indole inhibitors of human nonpancreatic secretory phospholipase A(2) .2. Indole-3-acetamides with additional functionality [J].

Dillard, RD ;

Bach, NJ ;

Draheim, SE ;

Berry, DR ;

Carlson, DG ;

Chirgadze, NY ;

Clawson, DK ;

Hartley, LW ;

Johnson, LM ;

Jones, ND ;

McKinney, ER ;

Mihelich, ED ;

Olkowski, JL ;

Schevitz, RW ;

Smith, AC ;

Snyder, DW ;

Sommers, CD ;

Wery, JP .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (26) :5137-5158

[7] Indole inhibitors of human nonpancreatic secretory phospholipase A(2) .1. Indole-3-acetamides [J].

Dillard, RD ;

Bach, NJ ;

Draheim, SE ;

Berry, DR ;

Carlson, DG ;

Chirgadze, NY ;

Clawson, DK ;

Hartley, LW ;

Johnson, LM ;

Jones, ND ;

McKinney, ER ;

Mihelich, ED ;

Olkowski, JL ;

Schevitz, RW ;

Smith, AC ;

Snyder, DW ;

Sommers, CD ;

Wery, JP .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (26) :5119-5136

[8] Indole inhibitors of human nonpancreatic secretory phospholipase A(2) .3. Indole-3-glyoxamides [J].

Draheim, SE ;

Bach, NJ ;

Dillard, RD ;

Berry, DR ;

Carlson, DG ;

Chirgadze, NY ;

Clawson, DK ;

Hartley, LW ;

Johnson, LM ;

Jones, ND ;

McKinney, ER ;

Mihelich, ED ;

Olkowski, JL ;

Schevitz, RW ;

Smith, AC ;

Snyder, DW ;

Sommers, CD ;

Wery, JP .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (26) :5159-5175

[9]

Feyfant E, 2011, METHODS MOL BIOL, V685, P241, DOI 10.1007/978-1-60761-931-4_12

[10]

Gasteiger J., 1990, Tetrahedron Comput. Meth, V3, P537, DOI 10.1016/0898-5529(90)90156-3

← 1 2 →