Investigation of emission plane control in GaInN/GaN multiple-quantum shells for efficient nanowire-based LEDs.

Significant attention has been directed toward core-shell GaInN/GaN multiple-quantum shell (MQS) nanowires (NWs) in the context of high-efficiency micro light-emitting diodes (micro-LEDs). These independent three-dimensional NWs offer the advantage of reducing the impact of sidewall etching regions. Furthermore, the emitting plane on the sidewalls demonstrates either nonpolar or semipolar orientation, while the dislocation density is exceptionally low. In this study, we assessed how changes in the NW morphology are affected by GaInN/GaN superlattice (SL) structures grown at varying growth temperatures, as well as control of the emission plane via the p-GaN shell and emission sizes. The SL growth rate was enhanced at elevated growth temperatures, accompanied by the shrinkage of the (0001)-plane and expansion of the (11̄01)-plane on the NWs. The samples exhibited a higher light output when the SLs were grown at elevated temperatures compared to those grown with lower temperatures. A similar trend was observed for the samples with a gradual temperature transition during the growth. These findings indicate that the dimensions of the (0001)-plane can be controlled through SL growth, which in turn influences the emission properties of NW-LEDs. In addition, the emission properties of NW-LEDs with different growth time p-GaN shells and different emission sizes were investigated. Based on the NW-LED characteristics, it was revealed that the weak emission of the (0001)-plane was the dominant factor for the limited light output, and the most effective way to realize high efficiency devices is to suppress current injection into the apex or minimize the grown (0001)-plane region. Overall, it is one promising way to control the emission planes of NWs, which holds significant relevance for the potential application of NW-LEDs in the realm of micro-LEDs.

Risk Factors for Radiation Necrosis and Local Recurrence after Proton Beam Therapy for Skull Base Chordoma or Chondrosarcoma.

[Proposal] Here, we retrospectively evaluate risk factors for radiation necrosis and local recurrence after PBT for skull base chordoma or chondrosarcoma. [Patients and Methods] We analyzed 101 patients who received PBT for skull base chordomas and chondrosarcomas from January 1989 to February 2021. Multivariable logistic regression models were applied for local recurrence, temporal lobe radiation necrosis rates, and temporal lobe radiation necrosis. [Results] In multivariate analysis, chordoma and large tumor size were independent significant factors for local recurrence. The 1-, 2-, 3-, 4- and 5-year local recurrence rates were 3.9%, 16.9%, 20.3%, 28.5% and 44.0% for chordoma and 0%, 0%, 0%, 0% and 7.1% for chondrosarcoma, respectively. The local recurrence rates of small tumors (<30 mm) were 4.3%, 14.7%, 17.7%, 17.7% and 25.9%, and those for large tumors were 3.6%, 15.1%, 19.2%, 32.7% and 59.6%, respectively. In multivariate analysis, BED Gy10 and total dose were risk factors for radiation necrosis. [Conclusions] For skull base chordoma and chondrosarcoma, the risk factors of local recurrence were chordoma and large tumor size, and those of radiation necrosis were BED Gy10 and total dose, respectively. DVH analysis is needed to investigate the risk factors for brain necrosis in more detail.

A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.

Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the Km for ATP. A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797. A fragment-based screen to identify new starting points for an EGFR inhibitor serendipitously identified a fragment that reacted with C775, a previously unexploited residue in the ATP binding pocket for a covalent inhibitor to target. A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 µM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition.

Abscopal effect with fever of unknown cause during radiotherapy: Two case reports and review of the literature.

The abscopal effect is a rare phenomenon that is defined as regression of tumor lesions distant from irradiation targets. At our department, two cases with an abscopal effect with fever of unknown cause (FUC) and an inflammatory response during radiotherapy were encountered. Radiotherapy is a local treatment; therefore, it rarely causes systemic side effects during radiotherapy, and if a patient develops a fever during radiotherapy, it is frequently considered tumor fever. We experienced 2 cases of FUC during irradiation followed by abscopal effect. The obvious relationship between the abscopal effect and the fever remains to be clarified. However, FUC during radiotherapy may be a hint to the abscopal effect, considering that immune response and cytokines are closely related to the abscopal effect.

Proton beam therapy for hepatocellular carcinoma with bile duct invasion.

AIM: Hepatocellular carcinoma (HCC) with bile duct invasion (BDI) (BDIHCC) has a poor prognosis. Moreover, due to the paucity of reports, there is no consensus regarding optimal management of this clinical condition yet. The aim of this study was to clarify the efficacy and safety of proton beam therapy (PBT) for BDIHCC. METHODS: Between 2009 and 2018, 15 patients with BDIHCC underwent PBT at our institution. The overall survival (OS), local control (LC), and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria of Adverse Events version 4.0. RESULTS: The median follow-up time was 23.4 months (range, 7.9-54.3). The median age was 71 years (range, 58-90 years). Many patients were Child A (n = 8, 53.3%) and most had solitary tumors (n = 11, 73.3%). Additionally, most patients had central type BDI (n = 11, 73%). The median tumor size was 4.0 cm (range, 1.5-8.0 cm). The 1-, 2-, and 3-year OS rates were 80.0%, 58.7% and 40.2%, respectively, and the corresponding LC and PFS rates were 93.3%, 93.3%, and 74.7% and 72.7%, 9.7%, and 0.0%, respectively. Acute grade 1/2 dermatitis (n = 7, 46.7%), and grades 2 (n = 1, 6.7%) and 3 (n = 1, 6.7%) cholangitis were observed. Late toxicities such as grade 3 gastric hemorrhage and pleural effusion were observed. No toxicities of grade 4 or higher were observed. CONCLUSIONS: PBT was feasible with tolerable toxicities for the treatment of BDIHCC.

Egg predators improve the hatching success of salamander eggs.

A common challenge that oviparous animals face is securing survivorship during the vulnerable embryonic stage. One of the parental investment strategies to improve survivorship is providing physical structures to protect the embryos. In amphibians, there is a notable diversity in jelly-layer structures surrounding eggs. Previous studies show that these jelly layers provide eggs with protection against egg predators, egg pathogens, and desiccation. However, few studies examined the cost-benefit relationship of the jelly-layer structures. By using the predator-prey interaction between wood frog (Lithobates sylvaticus) tadpoles and spotted salamander (Ambystoma maculatum) eggs as a model system, we tested three hypotheses: (1) having the outer jelly layers would be costly to the embryos, (2) the relative benefit of the structural egg defense would become apparent and increase as the intensity of egg predation increases, and (3) a certain degree of predation would increase the hatching success of salamander embryos by mechanically thinning the thick outer jelly layers and increasing oxygen diffusion throughout an egg mass. To test these hypotheses, we conducted a factorial experiment in which we crossed four egg-predation levels with two jelly-layer conditions, intact or removed. We found that the jelly layers were essential in protecting spotted salamander embryos from wood frog tadpoles but that the associated cost was apparent in no-predation treatments. The differential survivorship between intact eggs and eggs without jelly layers showed that the fitness advantage of jelly layers increased as the level of predation increased. Finally, the hatching success of intact egg masses was highest under the high predation conditions. These results imply that the evolution of the jelly-layer thickness occurred under constant egg-predation pressure. Given this predator-prey coevolution, egg predators may play a critical role in improving the hatching success of salamander embryos under certain conditions.

Fatigue Potentially Reduces the Effect of Transcranial Magnetic Stimulation on Depression Following COVID-19 and Its Vaccination.

COVID-19's long-term effects, known as Long-COVID, present psychiatric and physical challenges in recovered patients. Similarly, rare long-term post-vaccination side effects, resembling Long-COVID, are emerging (called Post-Vaccine). However, effective treatments for both conditions are scarce. Our clinical experience suggests that transcranial magnetic stimulation (TMS) often aids recovery in Long-COVID and Post-Vaccine patients. However, its effectiveness is reduced in patients with severe fatigue. Therefore, we retrospectively analysed Tokyo TMS Clinic's outpatient records (60 in total; mean age, 38 years) to compare Long-COVID and post-vaccine patients' characteristics and symptoms, assess the impact of TMS on their symptoms, and investigate the role of fatigue in depression recovery with TMS. The primary outcome was the regression coefficient of the initial fatigue score on depression score improvement using TMS. Secondary outcomes included psychiatric/physical scores before and after TMS and their improvement rates. We found no differences in the initial symptoms and background factors between Long-COVID and Post-Vaccine patients. After ten TMS sessions, all psychiatric and physical symptom scores improved significantly. TMS improves depression, insomnia, anxiety, and related neuropsychiatric symptoms, which were the primary complaints in this study. Thus, we conclude that TMS improves depression and anxiety. The effectiveness of TMS in treating depression in Long-COVID and Post-Vaccine patients decreased as fatigue severity increased. In conclusion, TMS relieved depressive symptoms following COVID-19 and vaccination; however, fatigue may hinder its effectiveness.

Activating mutations in EGFR and PI3K promote ATF4 induction for NSCLC cell survival during amino acid deprivation.

Some oncoproteins along with stress kinase general control non-derepressible 2 (GCN2) can ensure the induction of activating transcription factor 4 (ATF4) to counteract amino acid deprivation; however, little is known regarding the role of the oncogenic EGFR-PI3K pathway. In this study, we demonstrate that both mutated EGFR and PIK3CA contribute to ATF4 induction following GCN2 activation in NSCLC cells. The inhibition of EGFR or PI3K mutant proteins, pharmacologically or through genetic knockdown, inhibited ATF4 induction without affecting GCN2 activation. A downstream analysis revealed that the oncogenic EGFR-PI3K pathway may utilize mTOR-mediated translation control mechanisms for ATF4 induction. Furthermore, in NSCLC cells harboring co-mutations in EGFR and PIK3CA, the combined inhibition of these oncoproteins markedly suppressed ATF4 induction and the subsequent gene expression program as well as cell viability during amino acid deprivation. Our findings establish a role for the oncogenic EGFR-PI3K pathway in the adaptive stress response and provide a strategy to improve EGFR-targeted NSCLC therapy.

Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis.

Calorie restriction (CR) suppresses not only spontaneous but also chemical- and radiation-induced carcinogenesis. Our previous study revealed that the cancer-preventive effect of CR is tissue dependent and that CR does not effectively prevent the development of thymic lymphoma (TL). We investigated the association between CR and the genomic alterations of resulting TLs to clarify the underlying resistance mechanism. TLs were obtained from previous and new experiments, in which B6C3F1 mice were exposed to radiation at 1 week of age and fed with a CR or standard (non-CR) diet from 7 weeks throughout their lifetimes. All available TLs were used for analysis of genomic DNA. In contrast to the TLs of the non-CR group, those of the CR group displayed suppression of copy-neutral loss of heterozygosity (LOH) involving relevant tumor suppressor genes (Cdkn2a, Ikzf1, Trp53, Pten), an event regarded as cell division-associated. However, CR did not affect interstitial deletions of those genes, which were observed in both groups. In addition, CR affected the mechanism of Ikzf1 inactivation in TLs: the non-CR group exhibited copy-neutral LOH with duplicated inactive alleles, whereas the CR group showed expression of dominant-negative isoforms accompanying a point mutation or an intragenic deletion. These results suggest that, even though CR reduces cell division-related genomic rearrangements by suppressing cell proliferation, tumors arise via diverse carcinogenic pathways including inactivation of tumor suppressors via interstitial deletions and other mutations. These findings provide a molecular basis for improved prevention strategies that overcome the CR resistance of lymphomagenesis.

Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor.

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

The effects of road salt (NaCl), predation, and competition on the growth and community interactions of spotted salamanders (Ambystoma maculatum) and wood frogs (Lithobates sylvaticus).

Road deicing salts are frequently used in northern regions of the world during the winter and early spring months. As a result, a significant portion of road runoff into surrounding aquatic habitats contains road deicing salts. Previous studies found road salt contaminations in vernal pools that pond-breeding amphibians commonly use, including spotted salamanders (Ambystoma maculatum) and wood frogs (Lithobates sylvaticus). Studies have examined the impact of road salt on both amphibian species, but to our knowledge no previous studies have examined how road salt impacts the interspecific competition between both amphibians. We hypothesized that road salt would negatively impact growth and survivorship of both amphibian species. During the spring and summer of 2017, we conducted an outdoor mesocosm experiment in which we created eight experimental conditions with three main factors: presence/absence of NaCl (1000 mg/L Cl-), presence/absence of interspecific competition between the two amphibian species (A. maculatum and L. sylvaticus), and presence/absence of predatory dragonfly larvae (Family Libellulidae). Our experiment revealed that salt delayed hatching and increased deformity in spotted salamander hatchlings. Additionally, salt reduced salamander survivorship by 62% and frog survivorship by 30%. Wood frog tadpoles and road salt interacted to diminish salamander survivorship a further 80% beyond salt alone, likely through an increase in interspecific competition. Road salt increased the larval period of salamanders and decreased the proportion metamorphosed by the end of the experiment. Dragonfly larvae reduced salamander survivorship by 35%, whereas they increased wood frog tadpole development rates. Dragonfly larvae and salt interacted to alter tadpole denticle size, with salt negating the impact of dragonfly larvae. Thus, we found that salt interfered with aquatic predatory chemical cues. Overall, the results of this study suggest that management strategies should be implemented in order to reduce the impact of road salts on freshwater aquatic ecosystems.

Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring.

EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly selective EP300/CBP inhibitor, compound 11 (DS17701585), by scaffold hopping and structure-based optimization of a high-throughput screening hit 1. Compound 11 (DS17701585) shows dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model.

GZD824 Inhibits GCN2 and Sensitizes Cancer Cells to Amino Acid Starvation Stress.

Eukaryotic initiation factor 2α (eIF2α) kinase general control nonderepressible 2 (GCN2) drives cellular adaptation to amino acid limitation by activating the integrated stress response that induces activating transcription factor 4 (ATF4). Here, we found that a multikinase inhibitor, GZD824, which we identified using a cell-based assay with ATF4 immunostaining, inhibited the GCN2 pathway in cancer cells. Indeed, GZD824 suppressed GCN2 activation, eIF2α phosphorylation, and ATF4 induction during amino acid starvation stress. However, at lower nonsuppressive concentrations, GZD824 paradoxically stimulated eIF2α phosphorylation and ATF4 expression in a GCN2-dependent manner under unstressed conditions. Such dual properties conceivably arose from a direct effect on GCN2, as also observed in a cell-free GCN2 kinase assay and shared by a selective GCN2 inhibitor. Consistent with the GCN2 pathway inhibition, GZD824 sensitized certain cancer cells to amino acid starvation stress similarly to ATF4 knockdown. These results establish GZD824 as a multikinase GCN2 inhibitor and may enhance its utility as a drug under development. SIGNIFICANCE STATEMENT: GZD824, as a direct general control nonderepressible 2 (GCN2) inhibitor, suppresses activation of the integrated stress response during amino acid limitation, whereas it paradoxically stimulates this stress-signaling pathway at lower nonsuppressive concentrations. The pharmacological activity we identify herein will provide the basis for the use of GZD824 to elucidate the regulatory mechanisms of GCN2 and to evaluate the potential of the GCN2-activating transcription factor 4 pathway as a target for cancer therapy.

Revisiting biomolecular NMR spectroscopy for promoting small-molecule drug discovery.

Recently, there has been increasing interest in new modalities such as therapeutic antibodies and gene therapy at a number of pharmaceutical companies. Moreover, in small-molecule drug discovery at such companies, efforts have focused on hard-to-drug targets such as inhibiting protein-protein interactions. Biomolecular NMR spectroscopy has been used in drug discovery in a variety of ways, such as for the reliable detection of binding and providing three-dimensional structural information for structure-based drug design. The advantages of using NMR spectroscopy have been known for decades (Jahnke in J Biomol NMR 39:87-90, (2007); Gossert and Jahnke in Prog Nucl Magn Reson Spectrosc 97:82-125, (2016)). For tackling hard-to-drug targets and increasing the success in discovering drug molecules, in-depth analysis of drug-target protein interactions performed by biophysical methods will be more and more essential. Here, we review the advantages of NMR spectroscopy as a key technology of biophysical methods and also discuss issues such as using cutting-edge NMR spectrometers and increasing the demand of utilizing conformational dynamics information for promoting small-molecule drug discovery.

Crystal structure of the mineralocorticoid receptor ligand-binding domain in complex with a potent and selective nonsteroidal blocker, esaxerenone (CS-3150).

Activation of the mineralocorticoid receptor (MR) has long been considered a risk factor for cardiovascular diseases. It has been reported that the novel MR blocker esaxerenone shows high potency and selectivity for MR in vitro as well as great antihypertensive and renoprotective effects in salt-sensitive hypertensive rats. Here, we determined the cocrystal structure of the MR ligand-binding domain (MR-LBD) with esaxerenone and found that esaxerenone binds to MR-LBD in a unique manner with large side-chain rearrangements, distinct from those of previously published MR antagonists. This structure also displays an antagonist form that has not been observed for MR previously. Such a unique binding mode of esaxerenone provides great insight into the novelty, potency, and selectivity of this novel antihypertensive drug.

Preclinical Development of U3-1784, a Novel FGFR4 Antibody Against Cancer, and Avoidance of Its On-target Toxicity.

The FGFR4/FGF19 signaling axis is overactivated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects.U3-1784 is a high-affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.

A stable niche assumption-free test of ecological divergence.

Understanding the impact of geological events on diversification processes is central to evolutionary ecology. The recent amalgamation between ecological niche models (ENMs) and phylogenetic analyses has been used to estimate historical ranges of modern lineages by projecting current ecological niches of organisms onto paleoclimatic reconstructions. A critical assumption underlying this approach is that niches are stable over time. Using Notophthalmus viridescens (eastern newt), in which four ecologically diverged subspecies are recognized, we introduce an analytical framework free from the niche stability assumption to examine how refugial retreat and subsequent postglacial expansion have affected intraspecific ecological divergence. We found that the current subspecies designation was not congruent with the phylogenetic lineages. Thus, we examined ecological niche overlap between the refugial and modern populations, in both subspecies and lineage, by creating ENMs independently for modern and estimated last glacial maximum (LGM) newt populations, extracting bioclimate variables by randomly generated points, and conducting principal component analyses. Our analyses consistently showed that when tested as a hypothesis, rather than used as an assumption, the niches of N. viridescens lineages have been unstable since the LGM (both subspecies and lineages). There was greater ecological niche differentiation among the subspecies than the modern phylogenetic lineages, suggesting that the subspecies, rather than the phylogenetic lineages, is the unit of the current ecological divergence. The present study found little evidence that the LGM refugial retreat caused the currently observed ecological divergence and suggests that ecological divergence has occurred during postglacial expansion to the current distribution ranges.

Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors.

A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.

Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.).

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5 nM) and TNF-α production in mouse splenocytes (IC50=9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.