Programmable Retention Characteristics in MoS2-Based Atomristors for Neuromorphic and Reservoir Computing Systems.

In this study, we investigate the coexistence of short- and long-term memory effects owing to the programmable retention characteristics of a two-dimensional Au/MoS2/Au atomristor device and determine the impact of these effects on synaptic properties. This device is constructed using bilayer MoS2 in a crossbar structure. The presence of both short- and long-term memory characteristics is proposed by using a filament model within the bilayer transition-metal dichalcogenide. Short- and long-term properties are validated based on programmable multilevel retention tests. Moreover, we confirm various synaptic characteristics of the device, demonstrating its potential use as a synaptic device in a neuromorphic system. Excitatory postsynaptic current, paired-pulse facilitation, spike-rate-dependent plasticity, and spike-number-dependent plasticity synaptic applications are implemented by operating the device at a low-conductance level. Furthermore, long-term potentiation and depression exhibit symmetrical properties at high-conductance levels. Synaptic learning and forgetting characteristics are emulated using programmable retention properties and composite synaptic plasticity. The learning process of artificial neural networks is used to achieve high pattern recognition accuracy, thereby demonstrating the suitability of the use of the device in a neuromorphic system. Finally, the device is used as a physical reservoir with time-dependent inputs to realize reservoir computing by using short-term memory properties. Our study reveals that the proposed device can be applied in artificial intelligence-based computing applications by utilizing its programmable retention properties.

Rational Design of 3D Polymer Corona Interfaces of Single-Walled Carbon Nanotubes for Receptor-Free Virus Recognition.

Facing the escalating threat of viruses worldwide, the development of efficient sensor elements for rapid virus detection has never been more critical. Traditional point-of-care (POC) sensors struggle due to their reliance on fragile biological receptors and limited adaptability to viral strains. In this study, we introduce a nanosensor design for receptor-free virus recognitions using near-infrared (NIR) fluorescent single-walled carbon nanotubes (SWCNTs) functionalized with a poly(ethylene glycol) (PEG)-phospholipid (PEG-lipid) array. Three-dimensional (3D) corona interfaces of the nanosensor array enable selective and sensitive detection of diverse viruses, including Ebola, Lassa, H3N2, H1N1, Middle East respiratory syndrome (MERS), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), and SARS-CoV-2, even without any biological receptors. The PEG-lipid components, designed considering chain length, fatty acid saturation, molecular weight, and end-group moieties, allow for precise quantification of viral recognition abilities. High-throughput automated screening of the array demonstrates how the physicochemical properties of the PEG-lipid/SWCNT 3D corona interfaces correlate with viral detection efficiency. Utilizing molecular dynamics and AutoDock simulations, we investigated the impact of PEG-lipid components on 3D corona interface formation, such as surface coverage and hydrodynamic radius and specific molecular interactions based on chemical potentials. Our findings not only enhance detection specificity across various antigens but also accelerate the development of sensor materials for promptly identifying and responding to emerging antigen threats.

Electronic-grade epitaxial (111) KTaO3 heterostructures.

KTaO3 heterostructures have recently attracted attention as model systems to study the interplay of quantum paraelectricity, spin-orbit coupling, and superconductivity. However, the high and low vapor pressures of potassium and tantalum present processing challenges to creating heterostructure interfaces clean enough to reveal the intrinsic quantum properties. Here, we report superconducting heterostructures based on high-quality epitaxial (111) KTaO3 thin films using an adsorption-controlled hybrid PLD to overcome the vapor pressure mismatch. Electrical and structural characterizations reveal that the higher-quality heterostructure interface between amorphous LaAlO3 and KTaO3 thin films supports a two-dimensional electron gas with substantially higher electron mobility, superconducting transition temperature, and critical current density than that in bulk single-crystal KTaO3-based heterostructures. Our hybrid approach may enable epitaxial growth of other alkali metal-based oxides that lie beyond the capabilities of conventional methods.

Ultrasonographic examination of masticatory muscles in patients with TMJ arthralgia and headache attributed to temporomandibular disorders.

This study used ultrasonography to compare the thickness and cross-sectional area of the masticatory muscles in patients with temporomandibular joint arthralgia and investigated the differences according to sex and the co-occurrence of headache attributed to temporomandibular disorders (HATMD). The observational study comprised 100 consecutive patients with TMJ arthralgia (71 females and 29 males; mean age, 40.01 ± 17.67 years) divided into two groups: Group 1, including 86 patients with arthralgia alone (60 females; 41.15 ± 17.65 years); and Group 2, including 14 patients with concurrent arthralgia and HATMD (11 females; 33.00 ± 16.72 years). The diagnosis of TMJ arthralgia was based on the diagnostic criteria for temporomandibular disorders. The parameters of the masticatory muscles examined by ultrasonography were subjected to statistical analysis. The pain area (2.23 ± 1.75 vs. 5.79 ± 2.39, p-value = 0.002) and visual analog scale (VAS) score (3.41 ± 1.82 vs. 5.57 ± 12.14, p-value = 0.002) were significantly higher in Group 2 than in Group 1. Muscle thickness (12.58 ± 4.24 mm) and cross-sectional area (4.46 ± 2.57 cm2) were larger in the masseter muscle than in the other three masticatory muscles (p-value < 0.001). When examining sex-based differences, the thickness and area of the masseter and lower temporalis muscles were significantly larger in males (all p-value < 0.05). The area of the masseter muscle (4.67 ± 2.69 vs. 3.18 ± 0.92, p-value = 0.004) and lower temporalis muscle (3.76 ± 0.95 vs. 3.21 ± 1.02, p-value = 0.049) was significantly smaller in Group 2 than in Group 1. An increase in VAS was significantly negatively correlated with the thickness of the masseter (r = - 0.268) and lower temporalis (r = - 0.215), and the cross-sectional area of the masseter (r = - 0.329) and lower temporalis (r = - 0.293). The masseter and lower temporalis muscles were significantly thinner in females than in males, and their volumes were smaller in patients with TMJ arthralgia and HATMD than in those with TMJ arthralgia alone. HATMD and decreased masseter and lower temporalis muscle volume were associated with increased pain intensity.

Realization of Multiple Synapse Plasticity by Coexistence of Volatile and Nonvolatile Characteristics of Interface Type Memristor.

Studies on neuromorphic computing systems are becoming increasingly important in the big-data-processing era as these systems are capable of energy-efficient parallel data processing and can overcome the present limitations owing to the von Neumann bottleneck. The Pt/WOx/ITO resistive random-access memory device can be used to implement versatile synapse functions because it possesses both volatile and nonvolatile characteristics. The gradual increase and decrease in the current of the Pt/WOx/ITO device with its uniform resistance state for endurance and retention enables additional synaptic applications that can be controlled using electric pulses. If the volatile and nonvolatile device properties are set through rehearsal and forgetting processes, the device can emulate various synaptic behaviors, such as potentiation and depression, paired-pulse facilitation, post-tetanic potentiation, image training, Hebbian learning rules, excitatory postsynaptic current, and Pavlov's test. Furthermore, reservoir computing can be implemented for applications such as pattern generation and recognition. This emphasizes the various applications of future neuromorphic devices, demonstrating the various favorable characteristics of pulse-enhanced Pt/WOx/ITO devices.

Comparison of ultrasonography-based masticatory muscle thickness between temporomandibular disorders bruxers and temporomandibular disorders non-bruxers.

To compare masticatory muscle thickness in patients with temporomandibular disorders (TMDs) during rest and clenching, and by body position, using ultrasonography. This prospective study included 96 patients with TMD (67 females, 29 males; mean age: 40.41 ± 17.88 years): group 1, comprising 66 patients with TMD without bruxism (TMD_nonbruxer), and group 2, comprising 30 patients with concurrent TMD and bruxism (TMD_bruxer). In patients with TMD, bruxism was correlated with the presence of tinnitus, muscle stiffness, sleep problems, psychological stress, and restricted mouth opening. The masseter muscle significantly thickened during clenching (11.16 ± 3.03 mm vs 14.04 ± 3.47 mm, p < 0.001), whereas the temporalis muscle showed no significant increase in thickness from resting to clenching in an upright position (7.91 ± 1.98 vs 8.39 ± 2.08, p = 0.103). Similarly, during clenching in the supine position, the masseter muscle was significantly thicker compared with rest (11.24 ± 2.42 vs 13.49 ± 3.09, p < 0.001), but no significant difference was observed in temporal muscle thickness (8.21 ± 2.16 vs 8.43 ± 1.94, p = 0.464). In comparison between two groups, the average thickness of the masseter muscle was greater among TMD_bruxers than among TMD_nonbruxers in both the upright and supine positions (all p < 0.05). In the generalized lineal model, female sex (B = - 1.018, 95% confidence interval [CI] - 1.855 to - 0.181, p = 0.017) and bruxism (B = 0.868, 95% CI 0.567 to 1.169, p = 0.048) significantly predicted changes in masseter muscle thickness. Female sex (B = - 0.201, 95% CI - 0.299 to - 0.103, p = 0.011), increased age (B = - 0.003, 95% CI - 0.005 to 0.000, p = 0.038), and muscle stiffness (B = - 1.373, 95% CI - 2.369 to - 0.376, p = 0.007) were linked to decreased temporal muscle thickness. Comparing TMD nonbruxer and bruxer muscle thicknesses in upright and supine positions revealed significant increased thickness in the masseter muscle during clenching but not in the temporalis muscle. Masseter muscle thickness varied significantly by sex, body position, and resting/clenching, notably influenced by bruxism. These findings emphasize the relevance of these factors in clinical examinations of patients with TMD.

Surface triggered stabilization of metastable charge-ordered phase in SrTiO3.

Charge ordering (CO), characterized by a periodic modulation of electron density and lattice distortion, has been a fundamental topic in condensed matter physics, serving as a potential platform for inducing novel functional properties. The charge-ordered phase is known to occur in a doped system with high d-electron occupancy, rather than low occupancy. Here, we report the realization of the charge-ordered phase in electron-doped (100) SrTiO3 epitaxial thin films that have the lowest d-electron occupancy i.e., d1-d0. Theoretical calculation predicts the presence of a metastable CO state in the bulk state of electron-doped SrTiO3. Atomic scale analysis reveals that (100) surface distortion favors electron-lattice coupling for the charge-ordered state, and triggering the stabilization of the CO phase from a correlated metal state. This stabilization extends up to six unit cells from the top surface to the interior. Our approach offers an insight into the means of stabilizing a new phase of matter, extending CO phase to the lowest electron occupancy and encompassing a wide range of 3d transition metal oxides.

Strain Engineering in Perovskites: Mutual Insight on Oxides and Halides.

Perovskite materials have garnered significant attention over the past decades due to their applications, not only in electronic materials, such as dielectrics, piezoelectrics, ferroelectrics, and superconductors but also in optoelectronic devices like solar cells and light emitting diodes. This interest arises from their versatile combinations and physiochemical tunability. While strain engineering is a recognized powerful tool for tailoring material properties, its collaborative impact on both oxides and halides remains understudied. Herein, strain engineering in perovskites for energy conversion devices, providing mutual insight into both oxides and halides is discussed. The various experimental methods are presented for applying strain by using thermal mismatch, lattice mismatch, defects, doping, light illumination, and flexible substrates. In addition, the main factors that are influenced by strain, categorized as structure (e.g., symmetry breaking, octahedral distortion), bandgap, chemical reactivity, and defect formation energy are described. After that, recent progress in strain engineering for perovskite oxides and halides for energy conversion devices is introduced. Promising methods for enhancing the performance of energy conversion devices using perovskites through strain engineering are suggested.

Functional and analytical recapitulation of osteoclast biology on demineralized bone paper.

Osteoclasts are the primary target for osteoporosis drug development. Recent animal studies revealed the crucial roles of osteoblasts in regulating osteoclastogenesis and the longer lifespans of osteoclasts than previously thought with fission and recycling. However, existing culture platforms are limited to replicating these newly identified cellular processes. We report a demineralized bone paper (DBP)-based osteoblast culture and osteoclast assay platform that replicates osteoclast fusion, fission, resorption, and apoptosis with high fidelity and analytical power. An osteoid-inspired DBP supports rapid and structural mineral deposition by osteoblasts. Coculture osteoblasts and bone marrow monocytes under biochemical stimulation recapitulate osteoclast differentiation and function. The DBP-based bone model allows longitudinal quantitative fluorescent monitoring of osteoclast responses to bisphosphonate drug, substantiating significantly reducing their number and lifespan. Finally, we demonstrate the feasibility of humanizing the bone model. The DBP-based osteo assay platforms are expected to advance bone remodeling-targeting drug development with improved prediction of clinical outcomes.

Prognostic significance of senescence-related tumor microenvironment genes in head and neck squamous cell carcinoma.

The impact of the senescence related microenvironment on cancer prognosis and therapeutic response remains poorly understood. In this study, we investigated the prognostic significance of senescence related tumor microenvironment genes (PSTGs) and their potential implications for immunotherapy response. Using the Cancer Genome Atlas- head and neck squamous cell carcinoma (HNSC) data, we identified two subtypes based on the expression of PSTGs, acquired from tumor-associated senescence genes, tumor microenvironment (TME)-related genes, and immune-related genes, using consensus clustering. Using the LASSO, we constructed a risk model consisting of senescence related TME core genes (STCGs). The two subtypes exhibited significant differences in prognosis, genetic alterations, methylation patterns, and enriched pathways, and immune infiltration. Our risk model stratified patients into high-risk and low-risk groups and validated in independent cohorts. The high-risk group showed poorer prognosis and immune inactivation, suggesting reduced responsiveness to immunotherapy. Additionally, we observed a significant enrichment of STCGs in stromal cells using single-cell RNA transcriptome data. Our findings highlight the importance of the senescence related TME in HNSC prognosis and response to immunotherapy. This study contributes to a deeper understanding of the complex interplay between senescence and the TME, with potential implications for precision medicine and personalized treatment approaches in HNSC.

Red blood cell trapping using single-beam acoustic tweezers in the Rayleigh regime.

Acoustic tweezers (ATs) are a promising technology that can trap and manipulate microparticles or cells with the focused ultrasound beam without physical contact. Unlike optical tweezers, ATs may be used for in vivo studies because they can manipulate cells through tissues. However, in previous non-invasive microparticle trapping studies, ATs could only trap spherical particles, such as beads. Here, we present a theoretical analysis of how the acoustic beam traps red blood cells (RBCs) with experimental demonstration. The proposed modeling shows that the trapping of a non-spherical, biconcave-shaped RBC could be successfully done by single-beam acoustic tweezers (SBATs). We demonstrate this by trapping RBCs using SBATs in the Rayleigh regime, where the cell size is smaller than the wavelength of the beam. Suggested SBAT is a promising tool for cell transportation and sorting.

Vertically Integrated CMOS Ternary Logic Device with Low Static Power Consumption and High Packing Density.

A ternary logic system to realize the simplest multivalued logic architecture can enhance energy efficiency compared to a binary logic system by reducing the number of transistors and interconnections. For the ternary logic system, a ternary logic device to harness three stable states is needed. In this study, a vertically integrated complementary metal-oxide-semiconductor ternary logic device is demonstrated by monolithically integrating a thin-film transistor (TFT) over a transistor-based threshold switch (TTS). Because the TFT and the TTS have their own source (S), drain (D), and gate (G), there are physically six electrodes. But the hybrid ternary logic device of the TFT over the TTS has only four electrodes: S, D, GTFT, and GTTS like a single MOSFET. It is because the D of the underlying TTS is electrically tied with the S of the superjacent TFT. By combining an on- and off-state of the TFT and the TTS, ternary logic values of low current ("0"-state), middle current ("1"-state), and high current ("2"-state) are realized. Particularly, static power consumption at the "1"-state is decreased by employing the TTS with low off-state leakage current compared to previously reported other ternary logic devices. In addition, a footprint of the ternary logic device with the vertically overlaying structure that has a framework of "one over the other" can be lowered by roughly twice compared to that with the laterally deployed structure that has an organization of "one alongside the other".

Prospective Study of Nonsurgical Auricular Correction According to Timing of Treatment.

BACKGROUND AND PURPOSE: Many studies recommend nonsurgical auricular correction during the early postnatal period, when cartilage plasticity is high; however, many patients are not eligible for the procedure. This study compared different timings of nonsurgical auricular correction to investigate benefit after the optimal period for correction. METHODS: In this prospective study, 53 ears from 35 patients with congenital auricular anomaly were assigned to two groups according to age at correction: the "early-group" with correction within 2 weeks of birth and "late-group" with correction 8 weeks after birth. Aesthetic outcomes, caregiver satisfaction, detachment rates and mean device-wearing periods, were compared. RESULTS: Thirty-one ears from 20 patients comprised the early-group, and 18 ears from 12 patients comprised the late-group. Mean time to treatment after birth was 9.09 days in the early-group and 134.7 days in the late-group. In the early-group, detachment occurred in 4/31 ears (12.9%), and in the late-group, detachment occurred in 12/18 ears (66.7%), which was statistically significant (p<0.01). The average period of applying devices was 4.7 ± 1.2 weeks in the early-group and 8.5 ± 4.1 weeks in the late-group, with a significantly longer treatment time in the late-group (p=0.001). The early-group had 87.1% "good" results vs. 55.6% in the late-group, with a statistically significant difference. CONCLUSIONS: The correction period was shorter, detachment rate was lower, and treatment outcome was better in the early-group. However, successful correction was also present in the late-group, showing that the patients who have passed the optimum correction period should proceed after counselling.

Pan-cancer analysis reveals multifaceted roles of retrotransposon-fusion RNAs.

Transposon-derived transcripts are abundant in RNA sequences, yet their landscape and function, especially for fusion transcripts derived from unannotated or somatically acquired transposons, remains underexplored. Here, we developed a new bioinformatic tool to detect transposon-fusion transcripts in RNA-sequencing data and performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 3,088 normal tissue samples. We identified 52,277 cancer-specific fusions with ~30 events per cancer and hotspot loci within transposons vulnerable to fusion formation. Exonization of intronic transposons was the most prevalent genic fusions, while somatic L1 insertions constituted a small fraction of cancer-specific fusions. Source L1s and HERVs, but not Alus showed decreased DNA methylation in cancer upon fusion formation. Overall cancer-specific L1 fusions were enriched in tumor suppressors while Alu fusions were enriched in oncogenes, including recurrent Alu fusions in EZH2 predictive of patient survival. We also demonstrated that transposon-derived peptides triggered CD8+ T-cell activation to the extent comparable to EBV viruses. Our findings reveal distinct epigenetic and tumorigenic mechanisms underlying transposon fusions across different families and highlight transposons as novel therapeutic targets and the source of potent neoantigens.

Comparison of vertical bone resorption following various types of autologous block bone grafts.

BACKGROUND: This study aims to measure and compare the differences in vertical bone resorption after vertical augmentation using different types of autologous block bone. METHODS: Data were collected from 38 patients who had undergone vertical ridge augmentation using an autologous block bone before implant insertion. The patients were divided into three groups based on the donor sites: ramus bone (RB), chin bone (CB), and iliac crestal bone (IB). RESULTS: The surgical outcome of the augmentation was evaluated at the follow-up periods up to 60 months. In 38 patients, the mean amount of vertical bone gain was 8.36 ± 1.51 mm in the IB group, followed by the RB group (4.17 ± 1.31 mm) and the CB group (3.44 ± 1.08 mm). There is a significant difference in vertical bone resorption between the groups (p < 0.001), and the RB group demonstrated significantly lower resorption than the CB and IB groups (p = 0.011 and p < 0.001, respectively). The most common postoperative complications included neurosensory disturbance in the CB graft and gait disturbance in the IB graft. Out of the 92 implants inserted after augmentation, four implants were lost during the study period, resulting in an implant success rate of 95.65%. CONCLUSIONS: The RB graft might be the most suitable option for vertical augmentation in terms of maintaining postoperative vertical height and reducing morbidity, although the initial gain was greater with the IB graft compared to other block bones.

3D Neuromorphic Hardware with Single Thin-Film Transistor Synapses Over Single Thin-Body Transistor Neurons by Monolithic Vertical Integration.

Neuromorphic hardware with a spiking neural network (SNN) can significantly enhance the energy efficiency for artificial intelligence (AI) functions owing to its event-driven and spatiotemporally sparse operations. However, an artificial neuron and synapse based on complex complementary metal-oxide-semiconductor (CMOS) circuits limit the scalability and energy efficiency of neuromorphic hardware. In this work, a neuromorphic module is demonstrated composed of synapses over neurons realized by monolithic vertical integration. The synapse at top is a single thin-film transistor (1TFT-synapse) made of poly-crystalline silicon film and the neuron at bottom is another single transistor (1T-neuron) made of single-crystalline silicon. Excimer laser annealing (ELA) is applied to activate dopants for the 1TFT-synapse at the top and rapid thermal annealing (RTA) is applied to do so for the 1T-neuron at the bottom. Internal electro-thermal annealing (ETA) via the generation of Joule heat is also used to enhance the endurance of the 1TFT-synapse without transferring heat to the 1T-neuron at the bottom. As neuromorphic vision sensing, classification of American Sign Language (ASL) is conducted with the fabricated neuromorphic module. Its classification accuracy on ASL is ≈92.3% even after 204 800 update pulses.

Bone Marrow Adipocytes Contribute to Tumor Microenvironment-Driven Chemoresistance via Sequestration of Doxorubicin.

Chemoresistance is a significant problem in the effective treatment of bone metastasis. Adipocytes are a major stromal cell type in the bone marrow and may play a crucial role in developing microenvironment-driven chemoresistance. However, detailed investigation remains challenging due to the anatomical inaccessibility and intrinsic tissue complexity of the bone marrow microenvironment. In this study, we developed 2D and 3D in vitro models of bone marrow adipocytes to examine the mechanisms underlying adipocyte-induced chemoresistance. We first established a protocol for the rapid and robust differentiation of human bone marrow stromal cells (hBMSCs) into mature adipocytes in 2D tissue culture plastic using rosiglitazone (10 µM), a PPARγ agonist. Next, we created a 3D adipocyte culture model by inducing aggregation of hBMSCs and adipogenesis to create adipocyte spheroids in porous hydrogel scaffolds that mimic bone marrow sinusoids. Simulated chemotherapy treatment with doxorubicin (2.5 µM) demonstrated that mature adipocytes sequester doxorubicin in lipid droplets, resulting in reduced cytotoxicity. Lastly, we performed direct coculture of human multiple myeloma cells (MM1.S) with the established 3D adipocyte model in the presence of doxorubicin. This resulted in significantly accelerated multiple myeloma proliferation following doxorubicin treatment. Our findings suggest that the sequestration of hydrophobic chemotherapeutics by mature adipocytes represents a potent mechanism of bone marrow microenvironment-driven chemoresistance.

Long-Term Follow-Up of a Novel Surgical Option Combining Fibula Free Flap and 3D-Bioprinted, Patient-Specific Polycaprolactone (PCL) Implant for Mandible Reconstruction.

As the fibula free flap became the gold standard in mandibular reconstruction that required both hard tissue and soft tissue, various methods have been sought to solve the height discrepancy between the mandible and fibula. The purpose of this paper was to propose a surgical option that combined the microvascular fibula free flap with a 3D-bioprinted, patient-specific polycaprolactone (PCL) implant as a safe and simple novel method that achieved the best functional and aesthetic results in mandibular reconstruction surgery for young patients with malignant tumors. The patient's reconstructed mandible maintained volume symmetry without any deformation or complications for over 6 years. Computer-aided design/computer-aided manufacturing (CAD/CAM) and 3D printing technology enabled accurate and safe surgical results.

Ferroelectric synaptic devices based on CMOS-compatible HfAlOx for neuromorphic and reservoir computing applications.

The hafnium oxide-based ferroelectric tunnel junction (FTJ) has been actively researched because of desirable advantages such as low power and CMOS compatibility to operate as a memristor. In the case of HfAlOx (HAO), the remanent polarization (Pr) value is high and the atomic radius of Al is smaller than that of Hf; therefore, ferroelectricity can be better induced without mechanical force. In this paper, we propose an FTJ using HAO as a ferroelectric layer through electrical analysis and experiments; further, we experimentally demonstrate its capability as a synaptic device. Moreover, we evaluate the maximum 2Pr and TER value of the device according to the difference in conditions of thickness and cell area. The optimized device conditions are analyzed, and a large value of 2Pr (>∼43 µC cm-2) is obtained. Furthermore, we show that paired-pulse facilitation, paired-pulse depression, and spike-timing-dependent plasticity can be utilized in HAO-based FTJs. In addition, this study demonstrates the use of an FTJ device as a physical reservoir to implement reservoir computing. Through a series of processes, the synaptic properties of FTJs are verified for the feasibility of their implementation as an artificial synaptic device.

Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor.

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation of deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC50 = >10 µM) and showed potent inhibitory effects in cellular assay (IC50 = 3.5 ± 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).