Distinctive Sandwich-Type Composite Film and Deuterogenic Three-Dimensional Triwall Tubes Affording Concurrent Aeolotropic Conduction, Magnetism, and Up-/Down-Conversion Luminescence.

Compared to single functional materials, multifunctional materials with electrical conduction, magnetism, and luminescence are more attractive and promising, so it has become an important subject. A distinctive sandwich-type composite film (STCF) with dual-color up- and down-conversion luminescence, magnetism, and aeolotropic conduction is prepared by layer-by-layer electrospinning technology. Macroscopically, STCF is assembled by three tightly bonded layers, including a [polypyrrole (PPy)/poly(methyl methacrylate) (PMMA)]//[NaYF4:Yb3+, Er3+/PMMA] Janus nanobelt array layer as the first layer, a CoFe2O4/polyacrylonitrile (PAN) nanofiber nonarray layer as the second layer, and a Na2GeF6:Mn4+/polyvinylpyrrolidone (PVP) nanofiber nonarray layer as the third layer. This unique macropartition effectually confines conductive aeolotropy, magnetism, and luminescence in different layers. Microscopically, a Janus nanobelt is used as a construction unit to restrict the luminescent and conductive materials to their microregions, thus achieving highly conductive aeolotropy and green luminescence. The high integration of the micro-subarea and macro-subarea in the STCF can efficaciously avoid the mutual disadvantageous effects among different materials to obtain splendid polyfunctional performance. The conductive anisotropy and magnetism of the STCF can be adjusted by changing the contents of PPy and CoFe2O4. When the PPy content reaches 70%, the conductance ratio in the conductive direction to insulative direction is 108. The 2D STCF can be crimped by four different methods, and the 3D TWTs have the same excellent polyfunctional performances as 2D STCF. This unique design idea and construction technology can be applied to the preparation of other multifunctional materials to avoid harmful interference among various functions.

Discovery of macrocyclic HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM EC50s in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement.

SAR towards indoline and 3-azaindoline classes of IDO1 inhibitors.

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.

Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.

In Vitro Pharmacokinetic/Pharmacodynamic Modeling of HIV Latency Reversal by Novel HDAC Inhibitors Using an Automated Platform.

Antiretroviral therapy is able to effectively control but not eradicate HIV infection, which can persist, leading to the need for lifelong therapy. The existence of latently HIV-infected cells is a major barrier to the eradication of chronic HIV infection. Histone deacetylase inhibitors (HDACis), small molecules licensed for oncology indications, have shown the ability to produce HIV transcripts in vitro and in vivo. The pharmacologic parameters that drive optimal HIV latency reversal in vivo are unknown and could be influenced by such factors as the HDACi binding kinetics, concentration of compound, and duration of exposure. This study evaluates how these parameters affect HIV latency reversal for a series of novel HDACis that differ in their enzymatic on and off rates. Varying cellular exposure, using automated washout methods of HDACi in a Jurkat cell model of HIV latency, led to the investigation of the relationship between pharmacokinetic (PK) properties, target engagement (TE), and pharmacodynamic (PD) responses. Using an automated robotic platform enabled miniaturization of a suspension cell-based washout assay that required multiple manipulations over the 48 h duration of the assay. Quantification of histone acetylation (TE) revealed that HDACis showed early peaks and differences in the durability of response between different investigated HDACis. By expanding the sample times, the shift between TE and PD, as measured by green fluorescent protein, could be fully characterized. The comprehensive data set generated by automating the assays described here was used to establish a PK/PD model for HDACi-induced HIV latency reversal.

Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.

Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.

Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit 1 possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP98 via the strategic introduction of polar substitution, compound 13 was identified bearing a pyridyl oxetane core. Compound 13 demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.

Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy.

Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SNAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.

Synthesis of multifunctional rare-earth fluoride/Ag nanowire nanocomposite for efficient therapy of cancer.

Well-dispersed Ag nanowires and PVP-modified BaGdF5: Yb3+, Er3+ spherical nanoparticles were prepared by simple solvothermal and hydrothermal method, and they were further combined to obtain photo-thermal-magnetic multifunctional Ag/BaGdF5: Yb3+, Er3+ nanocomposites. Under NIR laser irradiation, monodispersed rare-earth fluoride BaGdF5: Yb3+, Er3+ in nanocomposite exhibit good upconversion fluorescent. Meanwhile, under the action of an external magnetic field, the nanocomposite also exhibits good magnetic properties and excellent contrast efficiency by CT/MR imaging. The NCs possess good structure and photothermal stability at multiple cycles due to that Ag nanowires are modified by polyvinyl pyrrolidone and sodium citrate. The biocompatibility and low toxicity of NCs are also remarkable. Importantly, the unique linear morphology of Ag particles can achieve high efficiency conversion between light and heat. Furthermore, in vitro tests also confirm the high efficiency of photothermal therapy for cancer cells.

Fabrication of NaYF4:Yb3+,Tm3+-modified Ag nanocubes with upconversion luminescence and photothermal conversion properties.

Herein, uniform Ag nanocube@NaYF4:Yb3+,Tm3+ multifunctional nanocomposites were constructed by a facile synthetic strategy. Following the successful synthesis of Ag nanocubes, cubic phase NaYF4:Yb3+,Tm3+ upconversion luminescent nanocrystals were modified on the surface of the Ag nanocubes, enhanced the mutual assistance of energy and versatility of the materials. Upon irradiation with a near-infrared laser, the nanocomposites exhibited excellent upconversion fluorescence and good photothermal conversion capability. Furthermore, the potential biological applications and biosafety of the Ag@NaYF4:Yb3+,Tm3+ nanocomposites were also demonstrated; the obtained nanocomposites could achieve a good bactericidal performance and photothermal treatment of cancer cells, and they could be potentially applied in the biomedical field as a promising agent. Furthermore, this method provides a facile approach for synthesizing a multifunctional nanocomposite with different properties.

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A.

Inhibition of NS5A has emerged as an attractive strategy to intervene in hepatitis C virus (HCV) replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with 50% effective concentrations (EC50s) of 1 to 4 pM in Huh7 or Huh7.5 cells bearing replicons for HCV genotype 1 (GT1) to GT7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs), with the exception of M28G. De novo resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31, and 93 across genotypes. Substitutions at position 93 were more common in GT1 to -4, while changes at position 31 emerged frequently in GT5 and -6. With the exception of GT4, the reintroduction of selected RASs conferred a ≥100-fold potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with an NS3/4A protease inhibitor (grazoprevir) and an NS5B polymerase prodrug (uprifosbuvir) was additive to synergistic, with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.

Integrating photoluminescence, magnetism and thermal conversion for potential photothermal therapy and dual-modal bioimaging.

Multifunctional nanocomposites (NCs) incorporating magnetic, luminescent and photothermal conversion properties are endowed with potential application in many fields such as imaging, tumor detection, drug delivery and therapy. Here, multifunctional MWCNTs-NaGdF4:Yb3+, Er3+, Eu3+ NCs, which offer the potential for integrated bioimaging and photothermal therapy (PTT) were fabricated by a facile hydrothermal method. The resulting sample exhibits uniform morphology, bright dual-modal luminescence and intrinsic paramagnetic properties. Under near-infrared laser excitation, NCs have excellent photothermal conversion properties. In addition, the MTT assay in HeLa cells shows that the NCs have good biocompatibility. Moreover, the up-conversion luminescence (UCL) imaging, X-ray computed tomography (CT) imaging and PTT in vitro of NCs were investigated. The results indicate that NCs can be used for dual-modal imaging-guided diagnose and PTT of cancer cells.

Development of a prodrug of hydantoin based TACE inhibitor.

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound.

Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors.

We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series.

Discovery of novel BTK inhibitors with carboxylic acids.

We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.

Modified Roux-en-Y gastric bypass for type 2 diabetes mellitus in China.

BACKGROUND/AIMS: This study aimed to evaluate the efficacy of modified Roux-en-Y gastric bypass for type 2 diabetes mellitus. METHODOLOGY: Forty-five type 2 diabetes mellitus patients underwent modified Roux-en-Y gastric bypass at WeiFang People's Hospital. Data on patient demographics, fasting plasma glucose (FPG), body mass index (BMI), medication use, remission and hemoglobin A1c (HbAlc) were prospectively collected and analyzed. RESULTS: At 6 months after surgery, all of these 45 patients obtained remission or a marked improvement. FPG was in the normal range in 39 (86.7%) patients stopping medicine treatment for their diabetes. Six patients (13.3%) had an obvious reduced abnormal FPG and they only required lower drug dosage. No statistically significant differences were found between the obese or non-obese groups (p=0.311). The mean BMI dropped from 28.9±3.0 kg/m2 to 27.4±2.8 kg/m2 (p=0.000) at the third month and 26.3±2.5 kg/m2 (p=0.000) at the sixth month. HbAlc decreased from their preoperative values of 7.4%±2.2% to 6.3%±1.5% (p=0.000) at the third month and 5.1%±0.9% (p=0.000) at the sixth month. CONCLUSIONS: Modified Roux-en-Y gastric bypass was effective in treating type 2 diabetes mellitus, independent of body mass index.

Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases.

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.

Biaryl substituted hydantoin compounds as TACE inhibitors.

We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.

Structure and activity relationships of tartrate-based TACE inhibitors.

The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.