Identification of oxazolidinediones and thiazolidinediones as potent 17ß-hydroxysteroid dehydrogenase type 3 inhibitors.

Novel and potent inhibitors of 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) were identified based on oxazolidinedione and thiazolidinedione derivatives, starting from a high-throughput screening hit, 5-(3-bromo-4-hydroxybenzyl)-3-(4-methoxyphenyl)-1,3-thiazol-2-one. 5-(3-Bromo-4-hydroxybenzylidene)-3-(4-methoxyphenyl)-2-thioxo-1,3-thiazolidin-4-one exhibited a promising activity profile and demonstrated significant selectivity over the related 17ß-HSD isoenzymes and nuclear receptors.

Discovery of potent and orally bioavailable 17ß-hydroxysteroid dehydrogenase type 3 inhibitors.

We have previously reported the discovery of a new class of potent inhibitors of 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) derived from benzylidene oxazolidinedione and thiazolidinedione scaffolds. In this study, these analogs were designed, synthesized, and evaluated in a human cell-based assay. The detailed structure-activity relationship (SAR) surrounding this pharmacophore were developed, and consequently a number of compounds from this series demonstrated single-digit nanomolar 17ß-HDS3 inhibitory activity in vitro. Subsequent optimization work in pursuit of the improvement of oral bioavailability demonstrated in vivo proof-of-concept by prodrug strategy based on phosphate esters for these 17ß-HSD3 inhibitors. When a phosphate ester 16 was administered orally at a high dose of 100mg/kg, 16 showed approximately two times more potent testosterone (T)-lowering effect against a positive control in the luteinizing hormone-releasing hormone (LH-RH)-induced T production assay. The T-lowering effect continued at ca 10% level of control over 4h after administration. The nonsteroidal molecules based on this series have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer.

Coumarins as novel 17beta-hydroxysteroid dehydrogenase type 3 inhibitors for potential treatment of prostate cancer.

The synthesis and SAR studies of 3- and 4-substituted 7-hydroxycoumarins as novel 17beta-HSD3 inhibitors are discussed. The most potent compounds from this series exhibited low nanomolar inhibitory activity with acceptable selectivity versus other 17beta-HSD isoenzymes and nuclear receptors.

The effect of serum on the proliferation of bone marrow-derived mesenchymal stem cells from aged donors and donors with or without chronic heart failure.

Many clinical studies of regenerative medicine using bone marrow-derived mesenchymal stem cells (MSCs) have been conducted globally. We initiated clinical studies using MSCs in 2001 and have now treated over 100 cases with patients aged 0-92 years. In a few cases involving patients with chronic heart failure (CHF), we observed that MSCs proliferated poorly. This contrasts with cell therapy studies wherein MSCs of patients with CHF were used for treatment. The effects of serum on the proliferation of MSCs from donors with normal heart function and with CHF have not been reported. Moreover, whether cell therapy is effective for elderly patients remains uncertain. Therefore, characterization of MSCs from aged donors and/or donors with CHF is urgently required. We retrospectively analysed the population doubling times (PDTs) of MSCs between the first and second passages. Although we had data for many samples of well-expanded MSCs from aged donors, a positive correlation was observed between donor age and PDT. A trend towards reduced variance in PDTs was observed in MSCs supplemented with fetal bovine serum (FBS) compared with those supplemented with autologous serum. When autologous serum was used, the average PDT of MSCs from donors with CHF was significantly longer than that of MSCs from donors without CHF. In contrast, when FBS was used, similar PDTs were observed in MSCs from donors with and without CHF. Thus, FBS promotes MSC expansion even from donors with CHF and MSC-based regenerative medicine might be feasible even for elderly patients. Copyright © 2016 John Wiley & Sons, Ltd.

Adipokine ganglioside GM2 activator protein stimulates insulin secretion.

Recently, we identified ganglioside GM2 activator protein (GM2AP) as a novel adipokine, and revealed that treatment of cultured cells with GM2AP impairs insulin signal transduction. The aim of this study was to examine the impact of GM2AP on glucose metabolism in vivo. Injection of recombinant GM2AP in mice significantly lowered blood glucose levels in glucose tolerance tests. Administration of GM2AP to mice for 10 days increased serum insulin levels, whereas the contents of glucose, leptin and FFA were significantly decreased. Stimulation of calcium influx and insulin secretion by GM2AP was observed in hamster insulinoma HIT-T15 cells. Blockage of GM2AP function by specific antibodies inhibited GM2AP-induced insulin secretion. These results provide novel insights into the physiological functions of GM2AP in obesity.