Biological Activity
lcq908 is a diacylglycerol acyltransferase-1 (dgat-1) inhibitor. dgat-1 has been recognized to catalyze the final committed step of processing dietary fatty acids into triglycerides carried on chylomicrons for transport around the body. thus,inhibition of dgat-1 represents a novel approach to treat metabolic disease.
in vitro
in vitro studies suggest that glucuronidation is the predominant metabolism pathway for elimination of lcq908 in humans. lcq908 inhibited bcrp-mediated efflux activity in a dose-dependent fashion with an ic50 value of 5 μm. lcq908 also inhibited oatp1b1, oatp1b3, and oat3 activity in a concentration-dependent manner with estimated ic50 values of 1.66 ± 0.95 μm, 3.34 ± 0.64 μm, and 0.973 ± 0.11 μm, respectively [1].
in vivo
lcq908 was fond to suppress the postprandial triglyceride levels in rats, dogs as well as monkeys. in rats whose lpl activity had been abolished, lcq908 reduced the postprandial accumulation of plasma triglyceride. additional, lcq908 decreased the postprandial rate of cm-tg secretion into the lymphatic duct and reduced the size of cms [2].
References
[1] kulmatycki k,hanna i,meyers d,salunke a,movva a,majumdar t,natrillo a,vapurcuyan a,rebello s,sunkara g,chen jevaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel dgat-1 inhibitor. int j clin pharmacol ther.2015 may;53(5):345-55.
[2] meyers cd, serrano-wu m, amer a, chen j, eric r, commerford r, et al. the dgat1 inhibitor pradigastat decreases chylomicron secretion and prevents postprandial triglyceride elevation in humans [abstract]j clin lipidol.2013;7:285.
[3] charles meyers, daniel gaudet, karine tremblay, ahmed amer, jin chen, feng aimin. the dgat1 inhibitor lcq908 decreases triglyceride levels in patients with the familial chylomicronemia syndrome. journal of clinical lipidology, vol 6, no 3, june 2012, 266-267.
