Diacylglyceride Oacyltransferases

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DGATs [35] along with acyl-CoA:monoacylglycerol acyltrasferase type 3 (MGAT3) [36] are the enzymes responsible for the completion of TG synthesis from an acyl-CoA and a diacylglyceride. Two isoforms of human DGAT are known. DGAT1 is located mainly in enterocytes in the small intestine and is primarily responsible for recombining dietary TGs upon absorption and for their incorporation into nascent chylomicrons for excretion [37,38]. DGAT2 is expressed primarily in liver, adipose tissue, and, to a lesser extent, the small intestine [39]. Both DGAT1 and DGAT2 have been highlighted as potential targets for small-molecule intervention [35]. TG synthesis is not the only role of the DGAT enzymes. DGAT1 is also responsible for retinol esterification, while DGAT2 is involved in the synthesis of wax esters [35].

High-fat diet studies with DGAT1-/- and DGAT1+/- mice demonstrated that the absence of DGAT1 activity may lead to increased insulin sensitivity, leptin sensitivity, protection against diet-induced obesity, and protection against liver steatosis [40-43].

DGAT2-/- mice suffer from severe hypolipidemia and do not survive postnatally [44]. However, this may be only a developmental phenomenon, since adult obese mice treated with DGAT2 antisense oligonucleo-tides were viable and showed improved hepatic steatosis along with improved insulin sensitivity [45].

Extensive research on small-molecule DGAT1 inhibitors began in the early 2000s. Several patent applications were published in 2004, exemplified by compounds 14 (IC50 < 10 nM, recombinant human DGAT1) and 15 [46,47]. These inspired several second-generation designs that retained the characteristic disubstituted cycloalkyl ring featuring a carboxylic acid. One research group reported the use of urea as a bioisostere for the aminobenzothiazole in 15, affording compound 16 with good potency (IC50 = 7 nM, recombinant human DGAT1), excellent rat PK properties (F = 55%, Clp = 0.04 L/h/kg, = 3.9 h), and which reduced plasma and liver TGs in a dose-dependent manner when administered to diet-induced obese (DIO) mice [48]. Another research group reported the use of a bicyclic system in place of frans-cyclohexyl ring, resulting in 17. Compound 17 was potent in a biochemical assay (IC50 = 15 nM, recombinant human DGAT1) as well as in a cell-based assay (IC50 3 nM, DGAT1 expressed in HuTu80 cells) and did not inhibit DGAT2. This compound also possessed favorable rat PK properties (F = 72%, Clp = 0.09 L/h/kg, ty2 = 7.0 h) and was shown to reduce plasma TGs in a dose-dependent manner in an oral lipid tolerance test in fasted rats and cause body weight reduction when administered to DIO mice [49].

Criture Cursive Flech
18 19 (PF-04620110)

An HTS followed by lead optimization of a resulting hit afforded a novel structural motif represented by ureido piperazine 18 that was potent in a biochemical assay (IC50 = 20 nM, recombinant human DGAT1) as well as in a cell-based assay (IC50 = 80 nM, DGAT1 expressed in 3T3-L1 cells) [50]. Compound 18 reduced adiposity and improved insulin sensitivity based on an oral glucose tolerance test after chronic administration to C56Bl6 mice maintained on a high-fat diet. However, untoward side effects of sebaceous gland atrophy and hair loss were observed. In a separate study, compound 18 decreased plasma TG levels and increased circulating GLP-1 levels in dogs after acute oral administration [50].

To date, one small-molecule DGAT inhibitor PF-04620110 (19) is reported to be undergoing clinical evaluation for treatment of type 2 diabetes. Compound 19 is a potent and selective DGAT1 inhibitor (IC50 = 19 nM, recombinant human DGAT1; IC50 = 28 nM, DGAT1 expressed in HT-29 cells; DGAT2 IC50 > 10 jmM) and was well tolerated in Phase I clinical trials [51].

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