Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based ß-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial.

Accumulation of amyloid ß peptides (Aß) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aß production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aß reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.

Skin disorder management in oral anticancer drugs by collaboration of hospital pharmacists and community pharmacists.

BACKGROUND: In Japan, the multidisciplinary team approach in cancer chemotherapy has become quite widespread. However, patients treated with oral anticancer drugs in outpatient clinics usually receive short medical examinations from doctors without any intervention of pharmacists. To improve this medical circumstance, we made a skin disorder manual for community pharmacists and evaluated its feasibility. METHODS: Patients who underwent oral skin toxic chemotherapy from May 1, 2017, to October 31, 2017, were enrolled. The severity of skin toxicities was evaluated based on NCI-CTCAE ver4.0. Skin care and skin disorders were assessed by community pharmacists based on the assessment document arranged by the investigator. Numbers of patients who replied to the assessment, numbers of replies, numbers of assessments and instructions for skin care, and numbers of prescription proposals were evaluated to assess the value of intervention of community pharmacists. RESULTS: Sixty-two patients were enrolled in this study. Community pharmacy responded to 55 patients (88.7%), for a total of 335 replies. The data described in the replies were as follows: 317 assessments of skin disorders (94.6%), 307 assessments of skin care (91.6%), 248 instructions for skin care (74%), and 19 prescription proposals (5.7%). CONCLUSIONS: Community pharmacists have high motivation for prevention and early detection of skin disorders. Although the number of prescription proposals is small, some proposals have contributed to improving side effects. Collaboration of hospital pharmacists and community pharmacists is important for prevention, early detection, and treatment of skin disorders caused by oral anticancer drugs.

Electrophoretic Separation on an Origami Paper-Based Analytical Device Using a Portable Power Bank.

The electrophoresis of ampholytes such as amino acids on a paper device is difficult because of the variation of pH distribution in time. On the basis of this observation, we propose a paper-based analytical device (PAD) with origami structure. By folding a filter paper, a low operation voltage of 5 V was achieved, where the power was supplied by a 5 V 1.5 A portable power bank through the USB type A receptacle. As a demonstration, we carried out the electrophoretic separation of pI markers (pI 5.5 and 8.7). The separation was achieved within 4 min before the pH distribution on the paper varied. Though the separation distance was small, it could be increased by expanding the origami structure. This result indicates that our proposed PAD is useful for electrophoretic separation on a paper device.

In vivo imaging of reactive oxygen species in mouse brain by using [3H]hydromethidine as a potential radical trapping radiotracer.

To assess reactive oxygen species (ROS) production by detecting the fluorescent oxidation product, hydroethidine has been used extensively. The present study was undertaken to evaluate the potential of the hydroethidine derivative as a radiotracer to measure in vivo brain ROS production. [(3)H]-labeled N-methyl-2,3-diamino-6-phenyl-dihydrophenanthridine ([(3)H]Hydromethidine) was synthesized, and evaluated using in vitro radical-induced oxidization and in vivo brain ROS production model. In vitro studies have indicated that [(3)H]Hydromethidine is converted to oxidized products by a superoxide radical (O(2)(•)-) and a hydroxyl radical (OH(•)-) but not hydrogen peroxide (H(2)O(2)). In vivo whole-body distribution study showed that [(3)H]Hydromethidine rapidly penetrated the brain and then was washed out in normal mice. Microinjection of sodium nitroprusside (SNP) into the brain was performed to produce ROS such as OH(•)- via Fenton reaction. A significant accumulation of radioactivity immediately after [(3)H]Hydromethidine injection was seen in the side of the brain treated with SNP (5 and 20 nmol) compared with that in the contralateral side. These results indicated that [(3)H]Hydromethidine freely penetrated into the brain where it was rapidly converted to oxidized forms, which were trapped there in response to the production of ROS. Thus, [(3)H]Hydromethidine should be useful as a radical trapping radiotracer in the brain.

Development of high-throughput spermidine synthase activity assay using homogeneous time-resolved fluorescence.

Spermidine synthase (SPDS) catalyzes transfer of the propylamine group from decarboxylated S-adenosylmethionine (dcSAM) to putrescine to yield methylthioadenosine (MTA) and spermidine. SPDS plays a regulatory role in cell proliferation and differentiation. This article describes the development of a high-throughput SPDS activity assay using homogeneous time-resolved fluorescence (HTRF) based on energy transfer from europium cryptate as a donor to crosslinked allophycocyanin (XL665) as an acceptor. First a highly specific anti-MTA monoclonal antibody, MTA-7H8, was generated, and then a competitive immunoassay for MTA determination was developed using europium cryptate-labeled MTA-7H8 and XL665-labeled MTA. In our homogeneous immunoassay, the percentage molar cross-reactivity of dcSAM with MTA-7H8 was 0.01% and the detection limit of MTA was 2.6 pmol/well. Our HTRF assay uses only one assay plate in which both enzyme reaction and MTA determination can be done successively. Therefore, our method can enable automatic screening of SPDS inhibitors from large numbers of samples.

Structure-activity relationships of a novel class of endothelin-A receptor antagonists and discovery of potent and selective receptor antagonist, 2-(benzo[1,3]dioxol-5-yl)-6-isopropyloxy-4-(4-methoxyphenyl)-2H-chromene-3-carboxylic acid (S-1255). 1. Study on structure-activity relationships and basic structure crucial for ET(A) antagonism.

A novel series of endothelin-A (ET(A)) selective receptor antagonists having a 2H-chromene skeleton are described. A lead compound, 2-(benzo[1,3]dioxol-5-yl)-2H-chromene-3-carboxylic acid (3), was found by modifications of our own angiotensin II antagonist. A structure-activity relationship (SAR) study of 3 reveals that the structural requirements essential for potent and selective ET(A) receptor binding affinity are the m,p-methylenedioxyphenyl, carboxyl, and isopropoxy groups at the 2-, 3-, and 6-positions, respectively, on the (R)-2H-chromene skeleton. The substituent at the 4-position is also important for improving the activity, and various hydrophobic functional groups of 6-9 A such as liner, branched, and cyclic aliphatic groups, unsubstituted and substituted aryl groups, and even halogen atoms were acceptable. These results suggest that (R)-2-(benzo[1,3]dioxol-5-yl)-6-isopropoxy-2H-chromene-3-carboxylic acid, formula 108, is the crucial basic structure to be recognized by the ET(A) receptor. The most potent compound is (R)-48 (S-1255), which binds to the ET(A) receptor with an IC(50) value of 0.19 nM and is 630-fold selective for the ET(A) receptor than for the ET(B) receptor. This compound has 55% oral bioavailability in rats. On the basis of the SAR, the roles of each substituent in the receptor binding are discussed.