A series of indolyl acrylamide derivatives was synthesized as potential diacylglycerol acyltransferase (DGAT) inhibitors. Furfurylamine containing indolyl acrylamide derivative 5h exhibited the most potent DGAT inhibitory activity using microsomes prepared from rat liver. Further evaluation against human DGAT-1 and DGAT-2 identified indolyl acrylamide analogues as selective inhibitors against human DGAT-2. In addition, the most potent compound 5h inhibited triglyceride synthesis dose-dependently in HepG2 cell lines.

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AC1497 is an effective dual inhibitor of malate dehydrogenase 1 and 2 targeting cancer metabolism. However, its poor aqueous solubility results in low bioavailability, limiting its clinical development. This study was conducted to develop an effective self-nanoemulsifying drug delivery system (SNEDDS) of AC1497 to improve its oral absorption. Based on the solubility of AC1497 in various oils, surfactants, and cosurfactants, Capryol 90, Kolliphor RH40, and Transcutol HP were selected as the components of SNEDDS. After testing various weight ratios of Capryol 90 (20–30%), Kolliphor RH40 (35–70%), and Transcutol HP (10–35%), SNEDDS-F4 containing 20% Capryol 90, 45% Kolliphor RH40, and 35% Transcutol HP was identified as an optimal SNEDDS with a narrow size distribution (17.8 ± 0.36 nm) and high encapsulation efficiency (93.6 ± 2.28%). Drug release from SNEDDS-F4 was rapid, with approximately 80% of AC1497 release in 10 min while the dissolution of the drug powder was minimal (<2%). Furthermore, SNEDDS-F4 significantly improved the oral absorption of AC1497 in rats. The maximum plasma concentration and area under the plasma concentration–time curve of AC1497 were, respectively 6.82- and 3.14-fold higher for SNEDDS-F4 than for the drug powder. In conclusion, SNEDDS-F4 with Capryol 90, Kolliphor RH40, and Transcutol HP (20:45:35, w/w) effectively improves the solubility and oral absorption of AC1497.

LW6 (3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester) is a potent inhibitor of drug efflux by the breast cancer resistance protein (BCRP). However, its poor aqueous solubility leads to low bioavailability, which currently limits in vivo applications. Therefore, the present study aimed to develop ternary solid dispersion (SD) formulations in order to enhance the aqueous solubility and dissolution rate of LW6. Various SDs of LW6 were prepared using a solvent evaporation method with different drug/excipient ratios. The solubility and dissolution profiles of LW6 in different SDs were examined, and F8-SD which is composed of LW6, poloxamer 407, and povidone K30 at a weight ratio of 1:5:8 was selected as the optimal SD. The structural characteristics of F8-SD were also examined using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). In the acidic to neutral pH range, F8-SD achieved rapid dissolution with a drug release of 76–81% within 20 min, while the dissolution of pure LW6 was negligible. The XRPD patterns indicated that F8-SD probably enhanced the solubility and dissolution of LW6 by changing the drug crystallinity to an amorphous state, in addition to the solubilizing effect of the hydrophilic carriers. Furthermore, F8-SD significantly improved the oral bioavailability of topotecan, which is a BCRP substrate, in rats. The systemic exposure of topotecan was enhanced approximately 10-fold by the concurrent use of F8-SD. In conclusion, the ternary SD formulation of LW6 with povidone K30 and poloxamer 407 appeared to be effective at improving the dissolution and in vivo effects of LW6 as a BCRP inhibitor.

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