Identification and characterization of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones as inhibitors of the fatty acid transporter FATP4

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 13, 2006, Pages 3504-3509

  Blackburn, Christopher ^a   Guan, Bing ^a   Brown, James ^a   Cullis, Courtney ^a   Condon, Stephen M ^a   Jenkins, Tracy J ^a   Peluso, Stephane ^a   Ye, Yingchun ^a   Gimeno, Ruth E ^a   Punreddy, Sandhya ^a   Sun, Ying ^a   Wu, Hui ^a   Hubbard, Brian ^a   Kaushik, Virendar ^a   Tummino, Peter ^a   Sanchetti, Praveen ^a   Yu Sun, Dong ^a   Daniels, Tom ^a   Tozzo, Effie ^a   Balani, Suresh K ^a   Raman, Prakash ^a   more..

^a MILLENNIUM PHARMACEUTICALS INC   (United States)

Author keywords

Biginelli condensation; FATP4 inhibitor; Fatty acid

Indexed keywords

3,4 DIHYDROPYRIMIDINE 2(1H) ONE; DIHYDROPYRIDINE DERIVATIVE; FATTY ACID; FATTY ACID TRANSPORT PROTEIN 4; LONG CHAIN FATTY ACID COENZYME A LIGASE; TETRAHYDROLIPSTATIN; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; CELL STRAIN HEK293; DRUG BIOAVAILABILITY; DRUG IDENTIFICATION; DRUG MECHANISM; DRUG PENETRATION; DRUG POTENCY; ENZYME INHIBITION; FATTY ACID TRANSPORT; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; LIPOPHILICITY; MOUSE; NONHUMAN; SMALL INTESTINE;

CELL LINE; FATTY ACID TRANSPORT PROTEINS; HUMANS; MOLECULAR STRUCTURE; PYRIMIDINONES; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33646829619     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.03.102     Document Type: Article

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29. 50 values were determined using the XL-fit software with vector-transfected cells as 100% inhibition control.
30. For example, plasma exposure data for compound 1p and two analogs in DIO in mice after 30 mg/kg oral dose are as follows: {A table is presented}
31. C57BL/6 male mice were placed on a 45% high fat diet for 1 week. After an overnight fast, FATP4 inhibitor 1p (racemic) or the lipase inhibitor orlistat (Xenical™), or vehicle was administered by oral gavage. Mice were then given access to food immediately after dosing. After 6 h, blood, stomach, small intestine (duodenum, jejunum, and ileum), other tissues and their contents were collected and analyzed for lipids and 1p.
32. In order for FATP4 inhibitors to distribute to the site of action (enterocytes) and to function at the intracellular active site, cell permeable compounds are required, (several compounds with attenuated permeabilities such as quaternary ammonium derivatives and high molecular weight symmetrical dimers were also prepared but none showed any FATP4 inhibitory activity; unpublished results). Subsequent distribution into the blood compartment may, however, be detrimental to efficacy; nonetheless, the residual high concentrations of 1p in intestinal tissues were thought to be sufficient to demonstrate proof of concept.
33. 7 This excess capacity will make it more difficult to detect inhibition in vivo. Furthermore, while compound 1p was able to inhibit fatty acid uptake in a transfected cell system, we have not yet assessed its ability to inhibit uptake in primary enterocytes in vitro using conditions that mimic the environment of the small intestine. Depending on the mechanism of inhibition, the potency of 1p may be significantly altered in the intestinal environment.