Design of Selective sPLA2-X Inhibitor (-)-2-{2-[Carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridine-2-yl}propanoic Acid

被引：5

作者：

Giordanetto, Fabrizio ^{[1
,8
]}

Knerr, Laurent ^{[1
]}

Nordberg, Peter ^{[1
]}

Pettersen, Daniel ^{[1
]}

Selmi, Nidhal ^{[1
]}

Beisel, Hans-Georg ^{[1
,9
]}

de la Motte, Hannah ^{[1
,10
]}

Mansson, Asa ^{[1
,11
]}

Dahlstrom, Mikael ^{[1
]}

Broddefalk, Johan ^{[1
]}

Saarinen, Gabrielle ^{[1
,12
]}

Klingegard, Fredrik ^{[1
,13
]}

Hurt-Camejo, Eva ^{[2
]}

Rosengren, Birgitta ^{[3
]}

Wikstrom, Johannes ^{[3
]}

Wagberg, Maria ^{[3
]}

Brengdahl, Johan ^{[5
]}

Rohman, Mattias ^{[5
]}

Sandmark, Jenny ^{[7
]}

Akerud, Tomas ^{[7
]}

Roth, Robert G. ^{[7
]}

Jansen, Frank ^{[6
]}

Ahlqvist, Marie ^{[4
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Med Chem, SE-43189 Gothenburg, Sweden

[2] AstraZeneca, IMED Biotech Unit, Translat Sci, SE-43189 Gothenburg, Sweden

[3] AstraZeneca, IMED Biotech Unit, Biosci, SE-43189 Gothenburg, Sweden

[4] AstraZeneca, IMED Biotech Unit, Drug Metab & Pharmacokinet, Cardiovasc & Metab Dis, SE-43189 Gothenburg, Sweden

[5] AstraZeneca, IMED Biotech Unit, Reagents & Assay Dev, SE-43189 Gothenburg, Sweden

[6] AstraZeneca, IMED Biotech Unit, Mechanist Biol & Profiling, SE-43189 Gothenburg, Sweden

[7] AstraZeneca, IMED Biotech Unit, Struct & Biophys, Discovery Sci, SE-43189 Gothenburg, Sweden

[8] DE Shaw Res, 120 W 45th St, New York, NY 10036 USA

[9] Medivir AB, SE-14122 Huddinge, Sweden

[10] Sweden Div Bioecon, RISE Res Inst, SE-41756 Gothenburg, Sweden

[11] Alfa Laval Lund AB, SE-22655 Lund, Sweden

[12] SCA Hyg Prod AB, SE-85188 Stockholm, Sweden

[13] SciLifeLab, Drug Discovery & Dev Platform, SE-17121 Solna, Sweden

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 07期

关键词：

Secreted phospholipase A2 type X; sPLA2-X; inhibitor; atherosclerosis; coronary artery disease; carotid ligation; GROUP-X; SECRETORY PHOSPHOLIPASE-A(2); ATHEROSCLEROSIS; ARTERY; A(2);

D O I：

10.1021/acsmedchemlett.7b00507

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A lead generation campaign identified indolebased sPLA(2)-X inhibitors with a promising selectivity profile against other sPLA(2) isoforms. Further optimization of sPLA(2) selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA(2)-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)-17 was tested in an ApoE(-/-) murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA(2)-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)-17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.

引用

页码：600 / 605

页数：11

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