[Hematologic Diseases and Neurological Complications].

Many hematologic diseases can be complicated by neurological symptoms during the disease course. Hematologic diseases can contribute to strokes and neuropathies; thus, neurologists should be aware of them. Recent reports have increased of neurological side effects associated with new anticancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor-T cell therapy. The relationship between hematologic diseases and neurological complications is expected to become more prevalent.

Analysis of the time-dependent changes of phospholipids in the brain regions of a mouse model of Alzheimer's disease.

Phospholipid levels are reported to be decreased in Alzheimer's disease (AD). For a better understanding, we investigated the time-dependent changes of phospholipids species in a mouse model of AD. The levels of phospholipids in the hippocampus and prefrontal cortex of wild-type and APP-Tg (J20) mice were measured by LC-ESI-MS/MS. Compared to wild-type, total phosphatidylcholine (PC), phosphatidylethanolamine (PE), and lysophosphatidylcholine (LPC) were Increased at 3 months but decreased at 6 months in the cortex of J20 mice. Total lysophosphatidylethanolamine (LPE) was decreased both at 3 and 6 months. PC was decreased and LPC was increased at 6 months, resulting in an increased LPC/PC ratio in the hippocampus of J20 mice. At species levels, PCA analysis could discriminate wild-type and J20 based on PC and LPC distribution at 6 months. At 6 months, several highly abundant PC including PC (16:0/16:0), PC (16:0/18:0), PC (16:0/18:1), and PC (18:0/18:1) were decreased in the cortex and hippocampus of J20. Conversely, LPC species including LPC 16:0, LPC 18:1, and LPC 20:4 were increased especially in the hippocampal area. Increased activation of phospholipid-metabolizing enzyme cPLA2 was seen in the hippocampus and cortex of J20 mice at 9 months. On the other hand, ROS levels started to increase as early as 3 months. Compared to 3 months, ROS levels were higher at 6 months in J20 mice. Thus, we demonstrated here a time- and area-dependent alteration of phospholipid composition during the early stage of AD, which could be important in understanding the pathological process.

Discovery of a benzimidazole series as the first highly potent and selective ACSL1 inhibitors.

Long-chain acyl-CoA synthetase-1 (ACSL1), an enzyme that catalyzes the synthesis of long-chain acyl-CoA from the corresponding fatty acids, is believed to play essential roles in lipid metabolism. Structure activity relationship studies based on HTS hit compound 1 delivered the benzimidazole series as the first selective and highly potent ACSL1 inhibitors. Representative compound 13 exhibited not only remarkable inhibitory activity against ACSL1 (IC50 = 0.042 µM) but also excellent selectivity for the other ACSL isoforms. In addition, compound 13 demonstrated an in vivo suppression effect against the production of long-chain acyl-CoAs in mouse.

Polymorphisms in Th17-related genes and the pathogenesis of autoimmune thyroid disease.

The prognosis of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's disease (HD) is difficult to predict. We previously suggested that Th17 cells may be associated with the pathogenesis of AITD. However, the association between gene polymorphisms in Th17-related genes and the prognosis of AITD was not clarified. To clarify this association, we genotyped 12 polymorphisms in 11 Th17-related genes (IL1Ra, IL6R, IL17R, IL21R, IL23R, CCR6, SOCS3, RORC, IL17A, IL17F and IL21) in 142 HD patients including 58 patients with severe HD and 48 patients with mild HD, 170 patients with GD including 81 patients with intractable GD and 49 patients with GD in remission, and 84 healthy volunteers. The frequency of the IL17F rs763780 T allele was higher in patients with severe HD than in patients with mild HD (p = .008). The frequency of the IL17R rs9606615 T allele was higher in patients with HD than in normal subjects (p = .011). The frequencies of the SOCS3 rs4969170 AA genotype, CCR6 rs3093024 AA genotype, and IL21 rs907715 AA genotype were higher in patients with intractable GD than in patients with GD in remission (p = .035, p = .002 and p = .030, respectively). In conclusion, IL17R rs9607715 and IL17F rs763780 polymorphisms are associated with the susceptibility and severity of HD, respectively. IL21 rs907715, SOCS3 rs4969170 and CCR6 rs3093024 polymorphisms are associated with the intractability of GD.

Association of the polymorphisms in Th2 chemotaxis-related genes with the development and prognosis of autoimmune thyroid diseases.

The prognosis of autoimmune thyroid disease (AITD) is difficult to predict. Th2 cells suppress the differentiation of Th1 and Th17 cells, which are associated with the prognosis of AITD. However, there are few reports as to whether Th2 chemotaxis-related genes, such as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), IL-25, TARC/CCL17 (Thymus and activation regulated chemokine/chemokine ligand 17) or STAT6 (Signal transducer and activator of transcription 6), affect the pathology of and/or susceptibility to AITD. Therefore, in this study, we genotyped functional SNPs in these genes to clarify the association of the genetic differences of genes related to Th2 differentiation and chemotaxis with the development and the prognosis of AITDs. The frequencies of the AA genotype of the CRTH2 rs545659 SNP and the CC genotype and the C allele of the CRTH2 rs634681 SNP were higher in patients with severe HD than in patients with mild HD. The frequency of the CC genotype in the TARC rs223828 SNP was higher in patients with intractable GD than in patients with GD in remission. In conclusion, the CRTH2 rs545659 and rs634681 SNPs were associated with the severity of HD, and the TARC/CCL17 rs223828 SNP was associated with the intractability of GD.

Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile.

Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.

Identification of a novel and orally available benzimidazole derivative as an NPY Y5 receptor antagonist with in vivo efficacy.

Optimization of lead compound 2 is described, mainly focusing on modification at the C-2 position of the benzimidazole core. Replacement of the phenyl linker of 2 with saturated rings resulted in identification of compound 8b which combines high Y5 receptor binding affinity with a good ADME profile leading to in vivo efficacy.

Design, synthesis and identification of novel benzimidazole derivatives as highly potent NPY Y5 receptor antagonists with attractive in vitro ADME profiles.

Optimization of our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole core, is described. Elimination of the flexible and metabolically labile -S-CH(2)- part and utilization of less lipophilic pyridone substructure led to identification of novel NPY Y5 receptor antagonists 6, which have low to sub-nanomolar Y5 receptor binding affinity with improved CYP450 inhibition profiles, good solubilities and high metabolic stabilities.

Subtleties in GPCR drug discovery: a medicinal chemistry perspective.

Therapeutic effects through G protein-coupled receptors (GPCRs) are promoted by a full agonist, partial agonist, neutral antagonist or inverse agonist. Dramatic change of function such as from a neutral antagonist to a full agonist with minimal variation of ligand structure is a phenomenon that medicinal chemists often encounter. This is also influenced by a change of assay format. The subtle nature of structure-function relationships is difficult to grasp unless carefully considered from both chemistry and assay perspectives. In this article we discuss the subtle aspects of GPCR drug discovery from the medicinal chemistry perspective.

Hit to lead SAR study on benzoxazole derivatives for an NPY Y5 antagonist.

We report a hit to lead study on a novel benzoxazole NPY Y5 antagonist. Starting from HTS hit 1, structure-activity relationships were developed. Compound 12 showed reduction of food intake and a tendency to suppress body weight gain over the 21-day experimental period.

Discovery of novel 5-alkynyl-4-anilinopyrimidines as potent, orally active dual inhibitors of EGFR and Her-2 tyrosine kinases.

5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure-activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model.