Identification and characterization of 4-aryl-3,4-dihydropyrimidin2(1H)-ones as inhibitors of the fatty acid transporter FATP4

被引：78

作者：

Blackburn, C

Guan, B

Brown, J

Cullis, C

Condon, SM

Jenkins, TJ

Peluso, S

Ye, YC

Gimeno, RE

Punreddy, S

Sun, Y

Wu, H

Hubbard, B

Kaushik, V

Tummino, P

Sanchetti, P

Sun, DY

Daniels, T

Tozzo, E

Balani, SK

Raman, P

机构：

[1] Millennium Pharmaceut Inc, Med Chem, Cambridge, MA 02139 USA

[2] Millennium Pharmaceut Inc, Metab Dis Biol, Cambridge, MA 02139 USA

[3] Millennium Pharmaceut Inc, DMPK, Cambridge, MA 02139 USA

来源：

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

关键词：

FATP4; inhibitor; fatty acid; Biginelli condensation;

D O I：

10.1016/j.bmcl.2006.03.102

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Several potent, cell permeable 4-aryl-dihydropyrimidinones have been identified as inhibitors of FATP4. Lipophilic ester substituents at the 5-position and substitution at the para-position (optimal groups being -NO2 and CF3) of the 4-aryl group led to active compounds. In two cases racemates were resolved and the S enantiomers shown to have higher potencies. (c) 2006 Elsevier Ltd. All rights reserved.

引用

收藏

页码：3504 / 3509

页数：6

相关论文

共 23 条

[1] Membrane proteins implicated in long-chain fatty acid uptake by mammalian cells: CD36, FATP and FABPm [J].

Abumrad, N ;

Coburn, C ;

Ibrahimi, A .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 1999, 1441 (01) :4-13

[2]

Abumrad N, 1998, J LIPID RES, V39, P2309

[3] Orlistat: its current status as an anti-obesity drug [J].

Ballinger, A ;

Peikin, SR .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2002, 440 (2-3) :109-117

[4] The fatty acid transport protein (FATP1) is a very long chain acyl-CoA synthetase [J].

Coe, NR ;

Smith, AJ ;

Frohnert, BI ;

Watkins, PA ;

Bernlohr, DA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (51) :36300-36304

[5] Targeted deletion of fatty acid transport protein-4 results in early embryonic lethality [J].

Gimeno, RE ;

Hirsch, DJ ;

Punreddy, S ;

Sun, Y ;

Ortegon, AM ;

Wu, H ;

Daniels, T ;

Stricker-Krongrad, A ;

Lodish, HF ;

Stahl, A .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (49) :49512-49516

[6] Characterization of the acyl-CoA synthetase activity of purified murine fatty acid transport protein 1 [J].

Hall, AM ;

Smith, AJ ;

Bernlohr, DA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (44) :43008-43013

[7] FATP1 channels exogenous FA into 1,2,3-triacyl-sn-glycerol and down-regulates sphingomyelin and cholesterol metabolism in growing 293 cells [J].

Hatch, GM ;

Smith, AJ ;

Xu, FY ;

Hall, AM ;

Bernlohr, DA .

JOURNAL OF LIPID RESEARCH, 2002, 43 (09) :1380-1389

[8] Mouse fatty acid transport protein 4 (FATP4): Characterization of the gene and functional assessment as a very long chain acyl-CoA synthetase [J].

Herrmann, T ;

Buchkremer, F ;

Gosch, I ;

Hall, AM ;

Bernlohr, DA ;

Stremmel, W .

GENE, 2001, 270 (1-2) :31-40

[9] A family of fatty acid transporters conserved from Mycobacterium to man [J].

Hirsch, D ;

Stahl, A ;

Lodish, HF .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (15) :8625-8629

[10] Unprecedented catalytic three component one-pot condensation reaction: An efficient synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones [J].

Hu, EH ;

Sidler, DR ;

Dolling, UH .

JOURNAL OF ORGANIC CHEMISTRY, 1998, 63 (10) :3454-3457