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Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.

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G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.Shortly after the identification of the human CD4 glycoprotein as the primary receptor for human immunodeficiency virus type 1 (HIV-1) (17,29,32,36), it became apparent that CD4 was not sufficient to mediate infection (1, 16, 18-21, 27-29, 34). HIV-1 attachment is mediated by the interaction of the viral envelope glycoprotein gp120 and its receptor CD4 on target cells. This binding induces a conformational change in gp120 that exposes a binding site for a coreceptor, usually of either the chemokine receptor CCR5 or CXCR4 (5, 51). Despite the significant success achieved with antiretroviral combination therapies, the emergence of resistant viruses and the lack of patient compliance stemming from adverse side effects and complex regimens have resulted in many therapeutic failures (50). Therefore, the development of better-tolerated antiretroviral agents that function through novel mechanisms and lack cross-resistance to the existing drugs is essential for the future management of HIV infections.The interaction of CCR5 with viral gp120 is critical for membrane fusion and virus entry because a blockade of such binding can inhibit HIV-1 infection efficiently (42). Viral glycoprotein and its receptor proteins are exposed at the viral and cell surfaces, respectively, and thus compounds that inhibit viral entry do not require high membrane permeability. In addition, coreceptors are encoded by cellular genes and so are not susceptible to mutations that would cause resistance to antiviral drugs. Therefore, virus entry is a promising target for the development of novel therapeutics (24), and a new generation of inhibitors of HIV-1 replication, based on the blockade of virus entry, is now in clinical trials and in various stages of development (10,23,30,37,40,41,45) Studies with SCH-C, the chemically related AD101...

The authors' purpose in this study was to assess the interactive effects of stressors, coping with stress, and self-efficacy on depression and anxiety in maintenance hemodialysis (HD) patients. Patients (n = 453) undergoing HD for more than 1 year in Japan were investigated. The regression lines illustrating significant (p < .05) interactions predict that itching HD patients with low self-efficacy will be more depressive and anxious than nonitching patients. In HD patients who report a high degree of emotion-oriented coping, itching patients will be more anxious than nonitching patients. These new findings may lead to the development of specific and focused interventions for depression or anxiety in maintenance HD patients.

Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays a role in the homeostasis of brain cholesterol by converting cholesterol to 24S-hydroxycholesterol (24HC). Despite a wide range of potential of CH24H as a drug target, no potent and selective inhibitors have been identified. Here, we report on the structure-based drug design (SBDD) of novel 4-arylpyridine derivatives based on the X-ray cocrystal structure of hit derivative 1b. Optimization of 4-arylpyridine derivatives led us to identify 3v ((4-benzyl-4-hydroxypiperidin-1yl)(2,4′-bipyridin-3-yl)methanone, IC 50 = 7.4 nM) as a highly potent, selective, and brain-penetrant CH24H inhibitor. Following oral administration to mice, 3v resulted in a dose-dependent reduction of 24HC levels in the brain (1, 3, and 10 mg/kg). Compound 3v (soticlestat, also known as TAK-935) is currently under clinical investigation for the treatment of Dravet syndrome and Lennox-Gastaut syndrome as a novel drug class for epilepsies.

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