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FXIa-6f is a high affinity, orally bioavailable macrocyclic FXIa inhibitor with antithrombotic activity in preclinical species. The objectives of this study were to characterize the in vitro metabolism, determine circulating metabolites in pre-clinical species, and examine the disposition of the compound in a bile duct-cannulated rat study (BDC) study to inform clinical development of the compound and the medicinal chemistry approach to identify molecules with improved properties. Across species, metabolic pathways included several oxidative metabolites, including hydroxylated metabolites on the macrocycle or P1 region, descarbamoylation of the methyl carbamate side chain, and a glutathione conjugate on the 2,6-difluoro-3-chlorophenyl ring. In BDC rat, the absorbed dose of [3H]FXIa-6f was cleared mainly by metabolism, with excretion of drug-related material in the bile, mostly as metabolites. In all preclinical species, the parent drug was the primary drug-related component in circulation, but the species differences in the metabolic pathways observed in vitro were reflected in the plasma, where M6, a descarbamoylated metabolite, was more prominent in rat plasma, and M9, a hydroxylated metabolite, was more prominent in monkey plasma. Based on the available data, the human metabolism appears to be most similar to monkey. [ABSTRACT FROM AUTHOR]

This annual review is the sixth of its kind since 2016 (see references). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation and bioactivation. These fields are constantly evolving with new molecular structures and discoveries of corresponding pathways for metabolism that impact relevant drug development with respect to efficacy and safety. Based on the selected articles, we created three sections: (1) drug design, (2) metabolites and drug metabolizing enzymes, and (3) bioactivation and safety (Table 1). Unlike in years past, more biotransformation experts have joined and contributed to this effort while striving to maintain a balance of authors from academic and industry settings. Table 1. Articles covered in this review. Title First author Source Drug design 1 Metabolic and pharmaceutical aspects of fluorinated compounds BM Johnson J Med Chem 63: 6315–6386, 2020 2 Effective application of metabolite profiling in drug design and discovery MA Cerny J Med Chem 63: 6387–6406, 2020 3 Understanding the metabolism of proteolysis targeting chimeras (PROTACs): the next step toward pharmaceutical applications L Goracci J Med Chem 63: 11615–11638, 2020 4 Late-stage lead diversification coupled with quantitative nuclear magnetic resonance spectroscopy to identify new structure-activity relationship vectors at nanomole-scale synthesis: application to loratidine, a human histamine H1 receptor inverse agonist MS Lall J. Med. Chem 63: 7268–7292, 2020 5 GLORYx: prediction of the metabolites resulting from phase 1 and Phase 2 biotransformations of xenobiotics Christina de Bruyn Kops Chem Res Toxicol 34: 286–299, 2021 Metabolites & drug metabolizing enzymes 6 Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202. P. Korprasertthaworn Biochem Pharmacol 169: 113616, 2019 7 Highly selective inhibition of tyrosine kinase (TYK2) for the treatment of autoimmune diseases: discovery of the allosteric inhibitor BMS-986165 ST Wrobleski ST J Med Chem 62: 8973–8995, 2019 8 Discovery of a Novel deaminated metabolite of a single-stranded oligonucleotide in vivo by mass spectrometry Jing Li Bioanalysis 11: 1955–1966, 2019 9 In vitro metabolism of 2′‐ribose unmodified and modified phosphorothioate oligonucleotide therapeutics using liquid chromatography mass spectrometry Jaeah Kim Biomedical Chromatography 34: e4839, 2020 10 Excretion, mass balance, and metabolism of [14C]LY3202626 in humans: an interplay of microbial reduction, reabsorption, and aldehyde oxidase oxidation that leads to an extended excretion profile K Katyayan Drug Metab Dispos 48: 698–707, 2020 11 Novel homodimer metabolites of GDC-0994 via cytochrome P450-catalyed radical coupling RH Takahashi Drug Metab Dispos 48: 521–527, 2020 12 Metabolism and disposition of volanesorsen, a 2'- O-(2 methoxyethyl) antisense oligonucleotide, across species. N Post Drug Metab Dispos 47: 1164–1173, 2019 Bioactivation and safety 13 Novel o-toluidine metabolite in rat urine associated with urinary bladder carcinogenesis Y Tajima Chem Res Toxicol 33: 1907–1914, 2020 14 Identifying cysteine, N-Acetylcysteine, and glutathione conjugates as novel metabolites of aristolochic acid I: emergence of a new detoxifying pathway J Zhang Chem Res Toxicol. 33: 1374–1381, 2020 15 Significance of multiple bioactivation pathways for meclofenamate as revealed through modeling and reaction kinetics MA Schleiff Drug Metab Dispos 49: 133–141, 2021 16 Detoxication versus bioactivation pathways of lapatinib in vitro: UGT1A1 catalyzes the hepatic glucuronidation of debenzylated lapatinib. DT Nardone-White Drug Metab Dispos 49: 233–244, 2021 17 Discovery of JNJ-63576253: a clinical stage androgen receptor antagonist for F877L mutant and wild-type castration-resistant prostate cancer (mCRPC) Z Zhang J Med Chem 64: 909–924, 2021 18 Bioactivation of α,β-unsaturated carboxylic acids through acyl-glucuronidation T Mulder Drug Metab Dispos 48: 819–829, 2020 19 Strategies to mitigate the bioactivation of aryl amines C Zhang Chem Res Tox 33: 1950 − 1959, 2020 20 Investigation of clozapine and olanzapine reactive metabolite formation and protein binding by liquid chromatography-tandem mass spectrometry T Geib Chem Res Tox 33: 2420–2431, 2020 21 Application of a rat liver drug bioactivation transcriptional response assay early in drug development that informs chemically reactive metabolite formation and potential for drug-induced liver injury JJ Monroe Toxicol Sci 177: 281–299, 2020 [ABSTRACT FROM AUTHOR]

This paper presents a class model for neutral-type bidirectional associative memory (BAM) neural networks (NNS) with infinite distributed delay. The model extends and improves some recent works for BAM-NNS. Based on the Lyapunov–Krasovskii functional (LKF) theory, the linear matrix inequality (LMI) method and some analysis techniques, the novel stability criteria for such model are obtained. Four numerical examples prove the validity and less conservativeness of the proposed criteria. The developed results are helpful to design of an actual system. [ABSTRACT FROM AUTHOR]

A novel tetrasiloxane-tailed surfactant bearing oligo(ethylene oxide) methyl ether and sugar moieties (TGA-2) has been evaluated. The dynamic surface tension (DST) and spreading properties imparted to water by TGA-2 have been investigated. DST parameters, namely effective diffusion coefficient, activation barrier, and contact angle have been calculated and analyzed. A general diffusion mechanism of surfactant TGA-2 has been delineated. DST analyses yielded significantly different long-term (DL) and short-term (DS) diffusion coefficients, implying that the adsorption process involves a mixed diffusion-kinetic mechanism. Adsorption activation energies (Ea) of the surfactant TGA-2 have been measured as 9.14 kJ/mol at 4 × 10−5 M and 19.37 kJ/mol at 4 × 10−4 M. These small Ea values suggest that the tetrasiloxane group is favorable for adsorption. A polytetrafluoroethylene (PTFE) membrane was chosen as a solid substrate to demonstrate the spreading ability imparted by TGA-2. At a TGA-2 concentration of 0.5% in water, the contact angle decreased from 57° to 7.8° in 60 s, such that the droplets became almost flat. [ABSTRACT FROM AUTHOR]

1. Due to its unique C-C and C-H bonding properties, conformational preferences and relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery to modulate potency and drug-like properties. During an effort to discover inhibitors of the hepatitis C virus non-structural protein 5B with improved potency and genotype-coverage profiles, the use of a pyrimidinylcyclopropylbenzamide moiety linked to a C6-substituted benzofuran or azabenzofuran core scaffold was explored in an effort to balance antiviral potency and metabolic stability. 2. In vitro metabolism studies of two compounds from this C6-substituted series revealed an NADPH-dependent bioactivation pathway leading to the formation of multiple glutathione (GSH) conjugates. Analysis of these conjugates by LC-MS and NMR demonstrated that the cyclopropyl group was the site of bioactivation. Based on the putative structures and molecular weights of the cyclopropyl-GSH conjugates, a multi-step mechanism was proposed to explain the formation of these metabolites by P450. This mechanism involves hydrogen atom abstraction to form a cyclopropyl radical, followed by a ring opening rearrangement and reaction with GSH. 3. These findings provided important information to the medicinal chemistry team which responded by replacing the cyclopropyl ring with a gem-dimethyl group. Subsequent compounds bearing this feature were shown to avert the bioactivation pathways in question. [ABSTRACT FROM AUTHOR]

Targeting aberrant tyrosine kinase activity may impact clinical outcome in acute myeloid leukemia (AML). We conducted a phase I study of the tyrosine kinase inhibitor midostaurin with bortezomib alone and in combination with chemotherapy in patients with AML. Patients on dose levels 1 and 2 (DL1 & 2) received midostaurin 50 mg bid and escalating doses of bortezomib (1 to 1.3 mg/m2). Patients on DL3 or higher received midostaurin and bortezomib following chemotherapy with mitoxantrone, etoposide, cytarabine (MEC). None of the patients enrolled to DL1 & 2 had dose-limiting toxicities (DLTs) or a clinical response. Among patients enrolled to DL3 or higher, DLTs were peripheral neuropathy, decrease in ejection fraction and diarrhea. A 56.5% CR rate and 82.5% overall response rate (CR + CR with incomplete neutrophil or platelet count recovery) were observed. The midostaurin/bortezomib/MEC combination is active in refractory/relapsed AML, but is associated with expected drug-related toxicities (NCT01174888). [ABSTRACT FROM AUTHOR]

In this paper, we reported an effective microfluidic-based method for fast continuous synthesis of monodisperse PEG/SiO2hybrid microspheres. The T-junction microfluidic chip equipped with rounded channels and the online photopolymerization system were applied for the microspheres microfabrication. The size of the microspheres was well controlled by the rounded channels and flow rate ratios of immiscrible fluids. We can obtain porous PEG microspheres when the hybrid microspheres were corroded by hydrofluoric acid. What's more, the interpenetrating polymer network structures of SiO2microspheres were obtained after the hybrid microspheres treated via a calcination process. [ABSTRACT FROM PUBLISHER]

Monodisperse silica microspheres have drawn much attention for having important applications in many areas. In this paper, a series of monodisperse silica (SiO2) microspheres was synthesized successfully using a modified Stöber method in which tetraethyl orthosilicate (TEOS) was continuously supplied into the reaction system by a syringe pump. By changing the supply rate of TEOS, the diameters of the obtained SiO2microspheres were controlled very well from 1 μm to 3 μm. Detailed characterization of the silica particles was performed using scanning electron microscopy (SEM). [ABSTRACT FROM AUTHOR]

Two new organic-inorganic hybrid materials based on Mo-polyoxometalates and N-heterocycle templates, namely [Ag3(DIE)6][Mo12O36·ClO4]2·Cl (1), and [(IM)4NH4] [Mo12O36·ClO4] (2) [DIE = 1,2-diimidazoloethane, IM = imidazole] have been hydrothermally synthesized and characterized by single-crystal X-ray diffraction. Compounds 1 and 2 possess the classical keggin-type heteropolyoxoanion with Cl as the center atom, and this is the first case. IR spectroscopy and gravimetric analysis were performed to further characterize these compounds. [ABSTRACT FROM PUBLISHER]

Monodisperse microsphere has drawn more and more attention in the past two decades. In order to synthesize it, an efficient procedure was employed by combining dispersion and seeding polymerizations together. The polymerization can be divided into two processes: nucleation and growth. Monodisperse polystyrene seed colloids with a diameter of 2 μm were synthesized in the nucleation process using dispersion polymerization, and then the seed colloids were swollen by monomer and further polymerized in the growth process. Finally, monodisperse polymer microspheres with an average diameter of 10 μm were obtained. [ABSTRACT FROM AUTHOR]

The self-assembly reaction of metal halides with DDTD dication (DDTD = 5,8 -Diazoniadispiro[4.2.4.2] tetradecane) yielded three novel organic-inorganic hybrid mental halides (DDTD)[Zn(N3)3Cl] (1), (DDTD)[Hg2Br6] (2), and (DDTD)[Cd4(N3)6(Cl)8] (3), which are characterized by X-ray crystallography and IR spectroscopy. The crystal structures of 1–3 show that they all crystallize in monoclinic systems. Compound 1 is mononuclear complex, compound 2 is binuclear complex, and compound 3 is a tetranuclear polymer. These compounds contained a variety of inorganic frameworks, due to the different coordinated modes of metal centers with halogen, which accordingly led to the change of the C-H···Cl(Br) interactions in the complexes. [ABSTRACT FROM AUTHOR]

MicroRNAs have been demonstrated to be deregulated in different types of cancer. miR-21 is a key player in the majority of cancers. Down-regulation of miR-21 in glioblastoma cells leads to repression of cell growth, increased cellular apoptosis and cell-cycle arrest, which can theoretically enhance the chemotherapeutic effect in cancer therapy. In this study, the poly(amidoamine) (PAMAM) dendrimer was employed as a carrier to co-deliver antisense-miR-21 oligonucleotide (as-miR-21) and 5-fluorouracil (5-FU) to achieve delivery of as-miR-21 to human glioblastoma cells and enhance the cytotoxicity of 5-FU antisense therapy. The inhibitory effect toward brain tumors was evaluated by MTT assay, and measurements of cell apoptosis and invasion using the human brain glioma cell line U251. PAMAM could be simultaneously loaded with 5-FU and as-miR-21, forming a complex smaller than 100 nm in diameter. Both the chemotherapeutant and as-miR-21 could be efficiently introduced into tumor cells. The co-delivery of as-miR-21 significantly improved the cytotoxicity of 5-FU and dramatically increased the apoptosis of U251 cells, while the migration ability of the tumor cells was decreased. These results suggest that our co-delivery system may have important clinical applications in the treatment of miR-21-overexpressing glioblastoma. [ABSTRACT FROM AUTHOR]

The preparation and performance of hypoxanthine (Hx) electrochemical biosensor, which was based on iron (III) meso-tetraphenylporphyrin (FeTPP) nanoparticles (NPs), is reported in this work. FeTPP NPs prepared by mixing solvent techniques with diameters ca. 25~45 nm and were used as a mediator. The XOD/FeTPPNP/GC electrode exhibited good amperometric signal for Hx. Based on the consumption of dissolved oxygen during the oxidation process of Hx catalyzed by the immobilized XOD, the biosensor could detect the concentration of Hx up to 0.34 mM with a detection limit of 1.0 µM. The usefulness of this biosensor for the analysis of real sample was also demonstrated by determining Hx in rat brain dialysate coupled with microdialysis. [ABSTRACT FROM AUTHOR]

Objective: To report the case of an individual with PHP, Turner syndrome and Hashimoto's thyroiditis. Case: A 16-year-old girl was referred to our hospital with chief complaint of short stature. She presented with round chubby facies, short neck, obesity and short stature. Radiography indicated short metatarsals and metacarpals, which mainly affected the second, third and fourth digits. Biochemistry revealed hyperphosphatemia, increased serum concentrations of parathyroid hormone and thyroid stimulating hormone, elevated levels of follicular-stimulating hormone and prolactin, and increased thyroid peroxidase antibody and thyroglobulin antibody. Radiographic examination revealed delayed bone age and pelvic ultrasonography demonstrated an immature uterus. Karyotype analysis showed 46,X,i(Xq10), while molecular analysis revealed a same sense mutation in exon 5 of GNAS (ATC → ATT, Ile).The specific diagnosis was made of Turner syndrome in the presence of Hashimoto's thyroiditis and PHP. She was treated with calcium supplementation, calcitriol and thyroxine. Conclusions: This is the first case report to describe a combination of Turner syndrome with these other clinical entities, and their co-existence should be considered and further investigated. [ABSTRACT FROM AUTHOR]

The crystals of the title compound were obtained from the reaction of (NH4)2MoO2S2, CuI, and {Butyltriethylammonium Bromide} in DMF solution. The cluster anion consists of two nest-shaped fragments interconnected through a four-membered Cu(I)2Cu ring. The structure of the cluster has been characterized by X-ray diffraction: Triclinic, space groupP–1; a = 11.9107(11) Å, b = 12.8125(12) Å, c = 13.0194(12) Å;α= 66.9650(10)°,β= 77.7370(10)°,γ= 88.4650(10)°; Volume = 1783.2(3)Å3; Z = 1. Supplemental materials are available for this article. Go to the publisher's online edition ofSynthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistryto view the supplemental file. [ABSTRACT FROM PUBLISHER]