ABT-046 is a novel, potent, selective, and orally bioavailableinhibitor of diacylglycerol acyltransferase 1 (DGAT-1 ) with IC50 of 8 nM. It was identified from a high-throughput screen against human DGAT-1. Oral administration 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, thus culminating in the nomination of 14 as clinical candidate ABT-046.
Physicochemical Properties
| Molecular Formula | C20H22N4O2 |
| Molecular Weight | 350.41428 |
| Exact Mass | 350.174 |
| CAS # | 1031336-60-3 |
| PubChem CID | 56933229 |
| Appearance | White to off-white solid powder |
| LogP | 4.308 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 26 |
| Complexity | 486 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | BWUXSHHOKODNAK-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C20H22N4O2/c21-20-17(12-22-18-9-10-23-24(18)20)16-7-5-15(6-8-16)14-3-1-13(2-4-14)11-19(25)26/h5-10,12-14H,1-4,11,21H2,(H,25,26) |
| Chemical Name | 2-[4-[4-(7-aminopyrazolo[1,5-a]pyrimidin-6-yl)phenyl]cyclohexyl]acetic acid |
| Synonyms | ABT-046; ABT 046; ABT046. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | ABT-046 can prevent the synthesis of triglycerides in HeLa cells that express human DGAT-1 with an IC50 of 78 nM, however it has no inhibitory impact on human DGAT-2[1]. When tested in Caco-2 cells, ABT-046 had high in vitro permeability values but no sign of active efflux (efflux ratios of 1.4 and 1.1 at 0.5 and 5 μM, respectively) [1]. In microsomal preparations from mouse and human livers, ABT-046 has very little turnover [1]. |
| ln Vivo | In CD-1 mice, ABT-046 (0.03-3 mg/kg; ig; once) dramatically lowers postprandial triglycerides [1]. In diet-induced obese mice, ABT-046 (0.3 mg/kg; ir; once) eliminates postprandial triglyceride fluctuations [1]. |
| Animal Protocol |
Animal/Disease Models: Male C57BL/6J diet-induced obesity (DIO) mice [1] Doses: 0.3 mg/kg Route of Administration: po (oral gavage), single dose Experimental Results: Serum triglyceride concentration continued to decrease throughout the experiment. Animal/Disease Models: CD-1 mice and SD (SD (Sprague-Dawley)) rats [1] Doses: 10 mg/kg or 5 mg/kg Route of Administration: intravenous (iv) (iv)injection or po (oral gavage) (pharmacokinetic/PK/PK analysis) Experimental Results: ABT-046a [1] Selected pharmacokinetic/PK/PK properties in mouse (10 mg/kg) Rat (5 mg/kg) ivb T1/2 (h) 4.6 3.8 Vss (L/kg) 0.3 0.3 Clp (L/h/ kg) 0.1 0.05 pob T1/2 (h) 5.1 5.6 Cmax (μg/mL) 17.4 9.3 AUC (μg·h/mL) 151 130 F (%) 78 91 a All values are mean ± SEM (unless otherwise Note, n = 3). b 1% Tween-80 aqueous solution. |
| References |
[1]. Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of Acyl-CoA: Diacylglycerol acyltransferase 1. J Med Chem. 2012 Feb 23;55(4):1751-1757. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~66.67 mg/mL (~190.26 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8538 mL | 14.2690 mL | 28.5380 mL | |
| 5 mM | 0.5708 mL | 2.8538 mL | 5.7076 mL | |
| 10 mM | 0.2854 mL | 1.4269 mL | 2.8538 mL |