The renin−angiotensin−aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound 26 was highly potent despite not occupying S1′−S2′ sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.

Abstract. Renal dysfunction is accelerated by various factors such as hypertension, aging and diabetes. Glomerular hyperfiltration, considered one of the major risk factors leading to diabetic nephropathy, is often encountered in diabetic patients. However, the interrelationship of these risk factors during the course and development of renal dysfunction has not been fully elucidated. In this study, the effects of aging and uninephrectomy (UNx)-induced hyperfiltration on renal changes were investigated in Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. In THM, the urinary albumin/creatinine (Alb/Cr) ratio was elevated with age without a concomitant increase in the plasma Cr concentration. Moreover, the urinary neutrophil gelatinase-associated lipocalin/Cr (NGAL/Cr) ratio, the renal monocyte chemoattractant protein-1 (MCP-1) mRNA expression and the renal collagen type I α 2 (COL1A2) mRNA expression were also increased with age. Age-related albuminuria in THM is likely caused by renal tubular damage, enhanced inflammatory response and tubulointerstitial fibrosis. Furthermore, following UNx, the urinary Alb̸Cr ratio and the plasma Cr concentration were increased in THM. The urinary NGAL/Cr ratio and the renal MCP-1 and COL1A2 mRNA expression were not affected by UNx. These results suggested that UNx-induced albuminuria in THM was caused by glomerular dysfunction, rather than renal tubular injury. In conclusion, this study demonstrated for the first time the effects of aging and UNx on renal changes in THM. These findings strongly reinforce the significance of applying a diversity of therapeutic approaches to the management of renal dysfunction. IntroductionChronic kidney disease (CKD) is a major public health concern worldwide because of the increasing prevalence of end-stage renal failure requiring dialysis or kidney transplantation and the increased risk of morbidity and mortality due to cardiovascular diseases (1-6). Aging leads to renal structural changes and functional decline. Imai et al (7) and Coresh et al (8) suggested that the prevalence of CKD increases with age. Moreover, a significantly higher prevalence of CKD was reported in hypertensive patients compared to normotensive subjects (8,9). High systemic blood pressure leads to pressure elevation in the glomerular capillaries, which is associated with renal vascular dysfunction. Elevated pressure in the glomerular capillaries results in glomerular sclerosis, increased albuminuria and decreased glomerular filtration rate (10). Furthermore, glomerular hyperfiltration is often observed during the early stages of diabetes and may contribute to the development of diabetic nephropathy (11,12). Thus, the progression of CKD is affected by various risk factors such as aging, hypertension and hyperfiltration. However, the interrelationship of individual risk factors during the course of renal dysfunction has not been fully elucidated.Tsukuba hypertensive mice (THM) are transgenic mice carrying both human renin and angiotensino...

This study reports the interfacial properties and lyotropic liquid crystal formation of sodium 1,2-bis{6-[4-(4-cyanophenyl)phenyloxy]hexyloxycarbonyl}ethanesulfonate (SBCPHS), which is a double-tail surfactant with cyanobiphenyl terminal groups, in water. Polarized microscopic observation of water/SBCPHS mixtures revealed the presence of columnar and lamellar phases. In the lamellar phase, myelin figures representing multilamellar tubes were observed, and some of these figures had a double-helix structure. In order to examine these liquid crystal structures in detail, the bilayer thickness of the lamellar tubes and the lattice parameters of the columnar phase were measured by small-angle X-ray scattering analysis. Four scattering peaks that could be ascribed to C2/m symmetry were observed for the columnar phase. The bilayer thickness and one of the lattice parameters were smaller than twice the molecular length of SBCPHS; this showed that the liquid crystal phases had intercalated structures. Comparison of SBCPHS with a typical double-tail hydrocarbon surfactant revealed that the cyanobiphenyl terminal groups in the former helped increase the stability of the liquid crystal formed at low temperatures. The stabilizing effect of the cyanobiphenyl terminal groups on the liquid crystals could have been driven by electrostatic intermolecular interactions between the terminal groups in antiparallel arrangement of the SBCPHS molecules.

Renin is the rate-limiting enzyme in the renin–angiotensin–aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative 4. In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered compound 18 (SPH3127), which demonstrated higher bioavailability and a more potent antihypertensive effect in preclinical models than aliskiren and has completed a phase II clinical trial for essential hypertension.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)is an endocrine disruptor that is known to have widespread effects on the reproductive system. We examined the effects of TCDD on testosterone production of primary cultured murine testicular cells. The cells, derived from the testes of ICR mice at age 65 days, were exposed to 10 -2 -10 4 pM TCDD for 3, 24, or 48 hr and treated with human chorionic gonadotropin for 6 hr to induce production of testosterone. At these concentrations of TCDD, the viability of testicular cells was not affected. No significant time-or TCDD concentration-dependent effects were observed on the secretion of testosterone. The data suggest that TCDD does not have a direct influence on testosterone production in the ICR mouse.