Preclinical PK investigation of a novel IDO1/TDO dual inhibitor-SHR9146 in mouse plasma and tissues by LC-MS/MS.

Purpose: The aim of the present study was to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of SHR9146, a novel IDO1/TDO dual inhibitor, in mouse plasma and tissues, and to apply it to investigate the preclinical plasma pharmacokinetics and tissue distribution of SHR9146 in mice. Methods: Samples were spiked with deuterated SHR9146-d4 as an internal standard and pretreated by protein-precipitation extraction with methanol. Chromatographic separation was performed on a Venusil ABS C18 column (150 × 4.6 mm, 5 µm) by isocratic elution with 10 mM ammonium acetate buffer containing 0.1% formic acid solution and methanol as mobile phases. MS detection was conducted in positive electrospray ionization with multiple reaction monitoring at m/z 444.1/229.4 for SHR9146 and m/z 448.4/229.2 for the internal standard. Results: The method showed good linearity in the calibration range from 0.05 to 50.0 µg/mL. Precisions (intra- and inter-run) were in the range from 0.5% to 5.1%, and accuracies (RE) were between -3.0% and 4.4% for all the concentration levels. SHR9146 was stable in all the tested bio-samples with recoveries >90%. Pharmacokinetic parameters were obtained by non-compartmental analysis. SHR9146 has a half-life of 0.713 h when IV-injected, with CL 12 mL/min/kg and Vd 0.666 L/kg. After oral dosing from 20 to 80 mg/kg, Cmax (range from 8.751 to 12.893 µg/mL) and AUC0-t (range from 15.606 to 69.971 µg·h/mL) of SHR9146 showed dose proportionality. Other post-oral pharmacokinetic parameters in plasma were as follows (n=6): Tmax 0.79 ± 0.36 h, t1/2 1.586 ± 0.853 h, CL 19.8 ± 0.9 mL/min/kg, Vd 3.427± 1.617 L/kg, and absolute bioavailability of 54.2% ± 12.6% (range from 40.2% to 64.7%). In addition, SHR9146 was found to be absorbed rapidly and distributed widely and mainly in the stomach, adrenal gland, liver, and lung. Conclusion: The method was simple, sensitive, accurate, and specific and was successfully applied for the preclinical pharmacokinetic and tissue distribution study of SHR9146 in mice. The results showed that SHR9146 had dose-independent kinetics in mice via oral administration and was absorbed rapidly and distributed widely. The study provides a good basis for further drug development assessment.

An LC-MS/MS method for quantification of HR011303, a novel highly selective urate transporter 1 inhibitor in beagle dogs and the application to a pharmacokinetic study.

HR011303 is a novel and highly selective urate transporter 1 (URAT1) inhibitor. In this study, a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantification of HR011303 in beagle dog plasma. Plasma samples were pretreated with protein-precipitation extraction by acetonitrile and added with a trifluoromethyl substituted analog of HR011303 as internal standard. The chromatographic separation was performed on a Shiseido C18 column (100 × 4.6 mm, i.d., 5 µm) by mobile phases consisting of 5 mm ammonium-formic acid (100:0.1) and acetonitrile-formic acid (100:0.1) solutions in gradient elution. The MS detection was conducted in electrospray positive ionization with multiple reactions monitoring at m/z 338 → 240 for HR011303 and m/z 328 → 230 for the internal standard using 25 eV argon gas collision induced dissociation. The established LC-MS/MS method showed good selectivity, sensitivity, precision and accuracy. The plasma pharmacokinetics of HR011303 in beagle dogs following both oral and intravenous administration were then successfully evaluated using this LC-MS/MS method.

Supramolecular hydrogels based on short peptides linked with conformational switch.

Short peptides appropriately linked with an azobenzene conformational switch were found to be motif and pH dependant supramolecular hydrogelators. The hydrogelation properties of the short peptides linked with the conformational switch were studied in detail with respect to dependence on amino acid residue, pH and salt effect. The presence of amino acids with aromatic side chains such as Phe and Tyr was found to be favorable for the short peptides to gel water at an appropriate pH range. Cationic amino acid residues such as Arg and Lys in the short peptides were found to be unfavorable for hydrogelation. pH and salt effect were also found to be important factors for the hydrogelation properties of the short peptides. A series of short peptides with bioactive sequences were linked with the conformational switch and their hydrogelation properties were investigated. Photoresponsive supramolecular hydrogels were realized based on the E-/Z- transition of the conformational switch upon light irradiation. Proper combination of amino acid residues in the short peptides resulted in smart supramolecular hydrogels with responses to multiple stimuli.

Chemistry and biological applications of photo-labile organic molecules.

Photo-labile molecules have been widely used not only in organic synthesis but also in biological study. The chemistry of the typical photo-labile organic molecules, including their structure, mechanism underlying their photo-lability and strategies to integrate them with biomolecules, is reviewed to illustrate the structural basis for photo-activable caged compounds. Biological applications of representative photo-labile caged molecules were also illustrated for a general understanding on the important roles of caged compounds in dynamic biological studies. This tutorial review would provide an interdisciplinary overview on the important area of chemical biological study making use of photo-labile caged compounds.

2-(tert-Butoxy-carbonyl-amino)-6-(1,3-dioxo-1H-2,3-dihydro-benzo[de]isoquinolin-2-yl)hexa-noic acid.

In the title naphthalimide derivative, C(23)H(26)N(2)O(6), the 1,8-naphthalimide system is essentially planar [maximum deviation = 0.0456 (16) Å]. A characteristic pattern of alternating long and short C-C bond lengths is observed in the 1,8-naphthalimide unit. The mean planes through the methyl carbamate and acetic acid groups form dihedral angles of 42.30 (9) and 61.59 (9)°, respectively, with the 1,8-naphthalimide plane. In the crystal structure, inter-molecular O-H⋯O and C-H⋯O hydrogen bonds link neighbouring mol-ecules, forming R(2) (2)(9) hydrogen-bond ring motifs. These rings are further inter-connected by inter-molecular N-H⋯O and C-H⋯O hydrogen bonds into a three-dimensional supra-molecular network.

Spiropyran-linked dipeptide forms supramolecular hydrogel with dual responses to light and to ligand-receptor interaction.

Integration of photo-sensitive spiropyran with dipeptide d-Ala-d-Ala in one small molecule resulted in a hydrogelator which can form supramolecular hydrogel with responses not only to light but to ligand-receptor interaction.