1796 (40). However, more long-term studies on the side effects and efficacy of cetilistat are required in order to confirm this and to answer the question whether GI side effects, such as steatorrhoea, are inevitably connected to the mechanism of action of this class. Another lipase inhibitor, called GT 389-255, was under development by Peptimmune, under a license from Genzyme. It was designed as a combination of an (undisclosed) lipase inhibitor and a polymer aiming to bind undigested triglycerides. This should allow increased fat excretion without the side effects of conventional lipase inhibitors. However, the development seems to be stalled or stopped, as there were no further clinical studies reported since the phase I trials conducted in 2004. Inhibitors of Intestinal Microsomal Triglyceride Transfer Protein (MTP) Microsomal triglyceride transfer protein (MTP) is an essential chaperone for the assembly of apolipoprotein B (apoB) (see (41) for recent review). The clinical utility of small-molecule MTP inhibitors to reduce plasma lipids was originally held up by their potential to induce hepatic steatosis, caused by inhibition of the hepatic form of MTP. However, further research led to the discovery of gut selective MTP inhibitors, which pre- dominantly act on the enterocytic form of MTP. This was achieved by compounds that are poorly absorbed or extensively metabolized to inactive metabolites (such as JNJ-16269110). A number of compounds have resulted from this development, but at this stage, their therapeutic potential is not yet clear. The company Aegerion is currently developing EGR-773, lomitapide (previously BMS-201038, Fig. 3) for the treatment of familial hypercholesterolemia, but apparently not for obesity. Pfizer stopped the development of their molecule dirlota- pide (Fig. 3) for human use and subsequently launched it in 2007 as the first drug approved for weight management in dogs. Surface Logix (http://www.surfacelogix.com) is currently working on SLx-4090 (structure not disclosed) for various indications, apparently including weight loss. The compound is presently in phase II. Johnson and Johnson recently reported a trial with their new MTP inhibitor JNJ-16269110 in 321 non-diabetic obese sub- jects. A dose-dependent weight loss of approximately 1.5– 3.5% (corrected for placebo) was obtained after 12 weeks of treatment (42). No significant side effects were reported, and treatment apparently did not lead to unpleasant fecal fat loss. DGAT1 and MGAT Inhibitors Diacylglycerol O-acyltransferase (DGAT; EC 2.3.1.20) catalyzes the last step of triacylgycerol synthesis. See (43) and (44) for Witkamp Fig. 3 Chemical structures of two representative MTP inhibitors: dirlotapide and lomitapide. reviews. DGAT is expressed in different tissues, including liver and white adipose tissue. Two isozymes of DGAT, DGAT1 and DGAT2, have been described so far (http://www.uniprot.org/uniprot). Increased DGAT2 ac- tivity has a role in steatosis, while DGAT1 plays a role in VLDL assembly. Increased plasma VLDL concentrations may promote obesity; thus, DGAT1 is considered a potential therapeutic target for obesity control. Pfizer recently (2010) finalized a phase I trial (Clintrial.gov NCT01064492) with their DGAT1 inhibitor PF 04620110 that is initially being developed for the treatment of type 2 diabetes mellitus. The company anticipates that the compound will have anti-diabetic effects through inhibition of intestinal triglyceride absorp- tion and will potentially cause weight loss. AstraZeneca (www.astrazeneca.com) also report a DGAT1 inhibitor in development for diabetes/obesity in their July 2010 pipeline overview (45). MGAT (MOGT 2; 2-acylglycerol O-acyltransferase 2; EC 2.3.1.22) catalyzes the formation of diacylglycerol from 2-monoacylglycerol and fatty acyl-CoA. It belongs to the diacylglycerol acyltransferase family (43,44). It is highly expressed in liver, small intestine, colon, stomach and kidney and plays a central role in absorption of dietary fat in the small intestine by catalyzing the re-synthesis of triacylglycerol in enterocytes. It is considered a potential target for weight loss, although concern has been raised because of the theoretical accumulation of fatty acids and monoacylglycerol in enterocytes. Probably due to this, MGAT gets less attention compared to SGAT, and its future as drug target seems uncertain.