Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia.

Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.

Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases.

The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing).

Patients' perception on the nutritional therapy for diabetic nephropathy.

Low protein diet (LPD) plays an important role in preventing the progression of diabetic nephropathy. However, it is a great burden to the patients. In this paper, we have studied the quality of life (QOL) in such patients. The study subjects were 59 patients (male 38, female 21) with type 2 diabetes. The patients were classified into tertiles based on their protein intake (g/kg BW). Scores from the diet-related QOL questionnaire were summarized by principal component analysis into four components; mental health, less burden, satisfaction and merit, and less social restriction. Higher protein intake was associated with less burden and less social restriction. In multiple regression analysis, the significant predictors for the "less burden" component were higher protein intake/BW and estimated glomerular filtration rate (eGFR). In summary, registered dietitians and clinicians must keep in mind that LPD is a serious burden to the patients and efforts must be made to minimize their burden in order to avoid discontinuation.

A novel highly potent autotaxin/ENPP2 inhibitor produces prolonged decreases in plasma lysophosphatidic acid formation in vivo and regulates urethral tension.

Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation. The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4-19 nM for recombinant autotaxin/ENPP2 proteins and 4.7-11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration. Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.

[Support of cancer patients by counseling].

Special counselors of consultation support centers at cancer hospitals have the difficult task of providing support to patients and families that receive the difficult diagnosis of cancer. Patients and their family first receive a notice and an explanation of the conditions of the disease, along with details of the standard future treatment policy in that country. Such information may not be conveyed by medical experts in a manner in which the patient can understand it, and very few patients are able to select a treatment plan on their own. With the support of a special counselor, the patient can determine the best way to manage the illness, and the counselor supports the decision-making process regarding the best treatment option. Moreover, support is offered to help the patient accept the diagnosis and maintain a balance of daily activities, which facilitate treatment continuation. With the intervention of a special counselor, problems that arise can be addressed directly and the counselor can summarize the patient's intentions and can act immediately to find solutions. Medical social workers understand that the patient is an individual who is concerned and who must be convinced and understand the situation in order to judge the situation and act accordingly. This approach gives courage to the patient, increases the will to live, and helps the patient regain a sense of self. A medical social worker's role is to help find answers and to suggest ideas for problem solving, to allow for patients to care for themselves and others.

Aureobasidium pullulans culture supernatant significantly stimulates R-848-activated phagocytosis of PMA-induced THP-1 macrophages.

Toll-like receptors (TLRs), which recognize a wide range of microbial pathogens and pathogen-related products, play important roles in innate immunology. Macrophages have a variety of TLRs, and pathogen binding to TLR resulted in the activation of macrophages. R-848, an immune response modifier, is an analog of imidazoquinoline derivative and binds to an endosome-localized TLR to exert an anti-viral response on leukocytes. In the present study, we verified that co-treatment of R-848 with other TLR agonists would enhance immune response. The culture supernatant of Aureobasidium pullulans (A. pullulans, which contains predominantly soluble ß-glucan), which binds to cell membrane-localized TLR, and to C-type lectin receptor Dectin-1, was treated together with R-848 to THP-1 macrophages. Compared to R-848 treatment alone, co-treatment of R-848 with A. pullulans culture supernatant significantly augmented TNF-α and IL-12p40 cytokine expression. Next, we investigated whether or not apoptotic cell uptake would be increased by co-treatment of R-848 with A. pullulans culture supernatant. To detect engulfed apoptotic cells, we induced apoptosis in human lymphoma Jurkat cells by 5-fluorouracil and stained them with fluorescent dye 5(6)-carboxytetramethylrhodamine (TAMRA), whereas THP-1 macrophage was labeled with fluorescein isothiocyanate-anti-CD14 and determined the percentage increase in TAMRA-positive THP-1 macrophages by flow cytometric assay. Since R-848 or A. pullulans treatment alone stimulated THP-1 macrophages to induce phagocytosis, co-treatment of R-848 with A. pullulans culture supernatant significantly augmented phagocytosis of apoptotic Jurkat cells. These results suggest that the activation of several different innate immune receptor pathways may enhance the immune response of R-848 significantly.

Structure-activity relationship studies of S1P agonists with a dihydronaphthalene scaffold.

Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P(1) agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P(3) agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P(1) agonistic activity with excellent selectivity over hS1P(3) and in vivo PLL activity in mice.

Discovery of S1P agonists with a dihydronaphthalene scaffold.

Structure-activity relationship of sphingosine-1-phosphate receptor agonists was examined. Cinnamyl derivative 1 was modified to improve S1P(1) agonistic activity as well as selectivity over S1P(3) agonistic activity. Dihydronaphthalene derivative 10d was identified as a potent S1P(1) receptor agonist with high selectivity against S1P(3) and enhanced efficacy in lowering peripheral lymphocyte counts in mice.

Cancer patients' distresses and inquiries: proposal of four-level classification based on consultation service and questionnaire survey.

The present study was undertaken to understand the realities of cancer patients' and their family members' distresses and inquiries, including medical/physical, emotional/spiritual and social/economic problems, from scientific viewpoints. The initial step of the study was to develop the classification category for these distresses and inquiries. The category was proposed based on information from two different sources; one is the consultation records of the Patient Support and Inquiry Division, Shizuoka Cancer Center and the other is the database of the Questionnaire Survey, which consisted of more than 25,000 distresses from 7885 people who faced up to cancer. The four-level classification category was constructed from 16 primary categories, 35 secondary categories, 129 tertiary categories and 619 quaternary categories. The classification category made it possible to analyze the distresses of cancer patients and their family members. The present study demonstrated the differences between the patterns of distresses for the consultation service and the questionnaire survey. In consultation centers belonging to hospitals, such as the Patient Support and Inquiry Division in the Shizuoka Cancer Center, patients wanted to consult on distresses and inquiries related to medical care. In contrast, they rarely consulted on emotional/spiritual or social problems. Based on the present classification category, we are developing a database called 'Questions and Answers for Cancer Patients' Distresses'. The database enables medical staff to learn what distresses patients and their family members, and to implement high-quality consultation in cancer clinics.