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Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment. In this study, BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD+ AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD+ AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy. Our results suggest that BPR1J-340 may be further developed in the preclinical and clinical studies as therapeutics in AML treatments. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A series of N -glucosyl indole derivatives bearing modifications at the C6-position of glucose was designed and synthesized. • All the synthesized derivatives were tested in vitro for their potential to inhibit the activity of hSGLT2. • Acethydrazide-containing N -glucosyl indole 9d was found to be the most active compound. • The selectivity, pharmacokinetic, and glucosuria potential of 9d were also studied. Abstract Sodium-dependent glucose co-transporter 2 (SGLT2) inhibition has been demonstrated to efficiently control hyperglycemia via an insulin secretion-independent pathway. The unique mode of action eliminates the risk of hypoglycemia and makes SGLT2 inhibitors an attractive option for the treatment of type 2 diabetes. In a continuation of our previous studies on SGLT2 inhibitors bearing different sugar moieties, sixteen new N -glucosyl indole derivatives were designed, synthesized, and evaluated for their inhibitory activity against hSGLT2. Of these sixteen, acethydrazide-containing N -glucosyl indole 9d was found to be the most potent SGLT2 inhibitor, and caused a significant elevation in urine glucose excretion in rats at 50 mg/kg, relative to the vehicle control. [ABSTRACT FROM AUTHOR]

Abstract: Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are the current focus on the indication for the management of hyperglycemia in diabetes. Here, a novel series of C-linked indolylxyloside-based inhibitors of SGLT2 has been discovered. Structure–activity relationship studies revealed that substituents at the 7-position of the indole moiety and a p-cyclopropylphenyl group in the distal position were necessary for optimum inhibitory activity. The pharmacokinetic study demonstrates that the most potent compound 1i is metabolically stable with a low clearance in rats. In further efficacy study, 1i is found to significantly lower blood glucose levels of streptozotocin (STZ)-induced diabetic rats. [Copyright &y& Elsevier]

Abstract A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8 , a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a - 29a exhibited superior potency against GT1b with GT1b EC 50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1 R ,2 S ,1′ R ,2′ S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC 50 = 0.003 nM) than daclatasvir (GT1b EC 50 = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC 50 > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection. Graphical abstract Image 1 Highlights • A novel class of dimeric phenylthiazole derivatives was identified as potent HCV NS5A inhibitors. • Several inhibitors showed GT1b potency at picomolar concentrations. • Compound 27a showed superior GT1b potency and promising pharmacokinetic properties in both rats and dogs. [ABSTRACT FROM AUTHOR]

Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N -indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N -indolylglycosides were synthesized and tested. A detailed structure–activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats. [ABSTRACT FROM AUTHOR]

Abstract: DB-67 and its lactone homolog DB-91 are derivatives of topoisomerase I inhibitor camptothecin (CPT) with silyl moiety, which may exhibit a slower inactivation process by changed kinetics of protein binding and/or hydrolysis of its lactone ring and result in increased antitumor activity and decreased toxicity. Pharmacokinetic properties and antitumor activities of the two silatecans were studied and compared. The lactone ring of DB-91 is more stable than those of all the other CPT derivatives in mouse plasma. Both silatecans were metabolized faster than CPT in mouse and human liver microsomes. Pharmacokinetic study revealed a plasma elimination half-life (t 1/2) of 33 and 94min for DB-67 and DB-91, respectively; similar systemic exposure in plasma between DB-67 and DB-91; and similar volume of distribution at the steady state between DB-67 and DB-91, approximately 15-fold smaller than that of CPT. While DB-91 showed limited activities, DB-67 exhibited activities against the growth of in vivo-like histocultured human tumors and s.c. xenografted human tumors in nude mice. In conclusion, DB-67 is more effective, compared to DB-91, against human tumor growth in in vitro, in vivo-like and in vivo systems. Further pre-clinical and clinical investigations of DB-67 are warranted. [Copyright &y& Elsevier]

Abstract: Paclitaxel is widely used to treat several types of solid tumors. The commercially available paclitaxel formulation contains Cremophor/ethanol as solubilizers. This study evaluated the effects of d-α-tocopheryl polyethylene glycol 400 succinate (TPGS 400) on the oral absorption of paclitaxel in mice. Mice were given an intravenous (18mg/kg) or oral (100mg/kg) dose of paclitaxel solubilized in Cremophor/ethanol or in TPGS 400/ethanol formulations. Paclitaxel plasma concentrations and pharmacokinetic parameters were determined. The maximal plasma concentrations of paclitaxel after an oral dose were 1.77±0.17 and 3.39±0.49μg/ml for Cremophor/ethanol and TPGS 400/ethanol formulations, respectively, with a similar time at 40–47min to reach the maximal plasma concentrations. The oral bioavailability of paclitaxel in TPGS 400/ethanol (7.8%) was 3-fold higher than that in Cremophor/ethanol (2.5%). On the other hand, the plasma pharmacokinetic profiles of intravenous paclitaxel demonstrated a superimposition for the two formulations. Furthermore, TPGS 400 concentration-dependently increased the intracellular retention of Rhodamine 123 in Caco-2 cells and enhanced paclitaxel permeability in monolayer Caco-2 cultures. TPGS 400 at concentrations up to 1mM did not inhibit testosterone 6β-hydroxylase, a cytochrome P450 isozyme 3A in liver microsomes metabolizing paclitaxel. Our results indicated that TPGS 400 enhances the oral bioavailability of paclitaxel in mice and the enhancement may result from an increase in intestinal absorption of paclitaxel. [Copyright &y& Elsevier]

Abstract: A rapid and sensitive liquid chromatography–tandem mass spectrometric method (LC–MS/MS) had been developed and validated to determine the concentrations of BPR0L075 in rat plasma. After a simple protein precipitation of plasma samples by acetonitrile, BPR0L075 was analyzed on a C8 column at a flow rate of 0.5mL/min. The mobile phase consisted of a mixture of 10mM ammonium acetate containing 0.1% formic acid and acetonitrile (20:80, v/v). Both BPR0L075 (analyte) and the internal standard (BPR0L092) were determined using electro-spray ionization and the MS data acquisition was via multiple reactions monitoring (MRM) in positive scanning model. The MS/MS ion transitions monitored are m/z 342.2/195.2 and 312.5/165.2 for BPR0L075 and BPR0L092, respectively. The low limit of quantitation was 0.5ng/mL. Each plasma sample was chromatographed within 5min. The method was validated with respect to linearity, accuracy, precision, recovery, and stability. A good linear relationship was observed over the concentration range of 0.5–1000ng/mL (r >0.9994). Absolute recoveries ranged from 63.45 to 68.34% in plasma at the concentrations of 2, 40, 400, and 800ng/mL. The intra- and inter-day accuracy ranged from 92.04 to 111.80%. Intra- and inter-day relative standard deviations were 1.08–3.29% and 1.96–5.46%, respectively. This developed and validated assay method had been successfully applied to a pharmacokinetic study after intravenous injection of BPR0L075 in rats at a dose of 5mg/kg. [Copyright &y& Elsevier]