ABT-046

Short Summary : DGAT-1 inhibitor,potent and selective

Category : Metabolism|DGAT

Purity : 0.98

CAS Number : 1031336-60-3

Formula : C20H22N4O2

Molecular Weight : 350.41

SMILE : NC1=C(C2=CC=C([C@@]3([H])CC[C@@](CC(O)=O)([H])CC3)C=C2)C=NC4=CC=NN41

Solubility : DMSO

Storage : Store at -20°C

Description : The final and only committed step in the synthesis of triglycerides is common to both major triglyceride biosynthesis pathways and is catalyzed by acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. DGAT-1, in particular, has received significant attention as a therapeutic target for cardiometabolic diseases. A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound ABT-046.In vitro: ABT-046 showed potent inhibition against both human and mouse isoforms of DGAT-1 (IC50 = 8 nM) and retained much of the high BE (BE = 23.1). Additionally, this compound showed no inhibition against human DGAT-2 and inhibited triglyceride formation in HeLa cells expressing human DGAT-1 with an IC50 of 78 nM. [1]. In vivo: Oral administration of ABT-046 at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels. Clinical trial: ABT-046 is currently in the preclinical developlent stage and no clinical data are available.Reference:[1] Yeh VS, Beno DW, Brodjian S, Brune ME, Cullen SC, Dayton BD, Dhaon MK, Falls HD, Gao J, Grihalde N, Hajduk P, Hansen TM, Judd AS, King AJ, Klix RC, Larson KJ, Lau YY, Marsh KC, Mittelstadt SW, Plata D, Rozema MJ, Segreti JA, Stoner EJ, Voorbach MJ, Wang X, Xin X, Zhao G, Collins CA, Cox BF, Reilly RM, Kym PR, Souers AJ. Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1. J Med Chem. 2012;55(4):1751-7.

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