DSR-71167, a novel mineralocorticoid receptor antagonist with carbonic anhydrase inhibitory activity, separates urinary sodium excretion and serum potassium elevation in rats.

Mineralocorticoid receptor (MR) antagonists, such as spironolactone (SPI) and eplerenone (EPL), are useful for treating hypertension and heart failure. However, these two agents have the serious side effect of hyperkalemia. We hypothesized that adding the ability to inhibit carbonic anhydrase (CA) would reduce the risk of hyperkalemia associated with MR antagonists. We investigated the profiles of DSR-71167 [2-([(2,2-difluoroethyl)amino]methyl)-2'-fluoro-N-(3-methoxy-4-sulfamoylphenyl)biphenyl-4-carboxamide hydrochloride; an MR antagonist with weak CA inhibitory activity] with regard to antimineralocorticoid actions by examining relationships between the urinary excretion of sodium (index of antimineralocorticoid action) in deoxycorticosterone acetate-treated rats and elevation of serum levels of potassium in potassium-loaded rats compared with a DSR-71167 derivative without CA inhibition (2-(hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide), SPI, and EPL. DSR-71167 dose-dependently increased urinary excretion of sodium in deoxycorticosterone acetate-treated rats without elevating serum levels of potassium in potassium-loaded rats. 2-(Hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide, SPI, and EPL elevated serum levels of potassium significantly in potassium-loaded rats at doses that increased MR inhibitory activity. We confirmed that DSR-71167 significantly increases urinary bicarbonate and decreases blood bicarbonate, as pharmacodynamic markers of CA inhibition, in intact rats. Chronic DSR-71167 administration showed antihypertensive effects in high salt-loaded Dahl hypertensive rats. These results demonstrate that DSR-71167 is a novel type of MR antagonist, with CA inhibitory activity, which is expected to become a safer MR antagonist with a low potential risk for hyperkalemia.

Structure-based optimization of cyclopropyl urea derivatives as potent soluble epoxide hydrolase inhibitors for potential decrease of renal injury without hypotensive action.

Epoxyeicosatrienoic acids (EETs) are known to have beneficial pharmacological effects on various cardiovascular events. However, EETs are biologically metabolized by soluble epoxide hydrolase (sEH) to less active metabolites. In our search for potent sEH inhibitors, we optimized a series of cyclopropyl urea derivatives and identified compound 38 as a potent sEH inhibitor with minimal CYP inhibition and good oral absorption in rats. Administration of 38 to DOCA-salt rats suppressed urinary albumin and MCP-1 excretion without affecting systolic blood pressure.

SM-368229, a novel promising mineralocorticoid receptor antagonist, shows antihypertensive efficacy with minimal effect on serum potassium level in rats.

The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist with partial agonistic activity, and spironolactone (SPI) on systolic blood pressure (SBP) and serum potassium in spontaneously hypertensive rats. SM-368229 given for 2 weeks prevented the increase in SBP without serum potassium elevation, but the treatment with SPI prevented SBP increase with serum potassium elevation. To elucidate the contribution of partial agonistic activity of SM-368229 for MR in the mitigation of serum potassium elevation, we studied the relationships between sodium balance decrease, as an index of antimineralocorticoid action, and serum potassium elevation in adrenalectomized and/or potassium-loaded rats, using SM-368229 and its derivatives (DSR-11861 and DSR-14397) showing different partial agonist activities for MR (12%, 0%, and 36%, respectively). DSR-11861 and SPI reversed sodium balance and increased serum potassium. SM-368229 also reversed sodium balance but did not show apparent serum potassium increase. Although DSR-14397 did not show serum potassium increase, its antimineralocorticoid action was very weak. These findings indicate that serum potassium elevation is negatively related to partial agonistic activities for MR, and SM-368229 shows antihypertensive efficacy with minimal effect on serum potassium level, probably due to its partial agonistic property.

Antihypertensive and cardiorenal protective effects of SM-368229, a novel mineralocorticoid receptor antagonist, in aldosterone/salt-treated rats.

The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist, on the blood pressure and cardiorenal injury markers in aldosterone/salt-treated hypertensive rats, in comparison to those of spironolactone (SPI). Uninephrectomized rats, given 1% NaCl to drink, were infused with aldosterone (0.75 µg/h, s.c.). In experiment 1, SM-368229 (10, 30 mg/kg) or SPI (100 mg/kg) were administered for 14 days immediately after aldosterone/salt loading. In experiment 2, SM-368229 (10 mg/kg) or SPI (100 mg/kg) were administered for 10 days after 10 days of aldosterone/salt loading. In both experiments, SM-368229 prevented the increase in systolic blood pressure, heart/kidney weights, and urinary protein/N-acetyl-ß-D- glucosaminidase excretion caused by aldosterone infusion. In real-time polymerase chain reaction analysis, SM-368229 abolished aldosterone-induced gene expression levels for inflammatory, fibrosis and oxidative stress markers in hearts and kidneys. The antihypertensive effect of SM-368229 (30 mg/kg) was superior to that of SPI, and the antihypertensive and cardiorenal protective effects of SM-368229 (10 mg/kg) were similar to those of SPI (100 mg/kg) in both experiments. These results clearly demonstrated that SM-368229 strongly attenuated the progression of hypertension and exerted cardiorenal protection in aldosterone/salt-treated hypertensive rats.

SM-368229, a novel selective and potent non-steroidal mineralocorticoid receptor antagonist with strong urinary Na+ excretion activity.

Mineralocorticoid receptor (MR) antagonists, such as spironolactone (SPI) and eplerenone (EPL), are useful for the treatment of hypertension and heart failure. However, the use of these two agents has been limited due to endocrine disturbance (SPI) and poor drug action (EPL). In our search for safer and more effective MR antagonists, we identified SM-368229 as a novel non-steroidal MR antagonist. SM-368229 showed strong MR inhibitory activity with IC(50) values of 0.021 and 0.13 µM in the binding assay and reporter-gene assay, respectively. The selectivity of SM-368229 for MR was 18-fold higher than that for other steroid receptors, such as androgen, progesterone, and glucocorticoid receptors. SM-368229 dose-dependently increased urinary Na(+)/K(+) ratio with an ED(50) value of 5.6 mg/kg in adrenalectomized rats treated with deoxycorticosterone acetate, and its efficacy was superior to that of SPI (ED(50) = 14 mg/kg) or EPL (ED(50) = 147 mg/kg). Moreover, even at high doses of 100 and 300 mg/kg, SM-368229 showed very weak anti-androgenic effect in methyltestosterone-treated male rats and no progestagenic effect in estrus cycle synchronized female rats. These findings indicate that SM-368229 may offer a new promising therapeutic option for the treatment of hypertension and heart failure.

[Proposal for Reduction Measures of Eye Lens Exposure Based on Actual Exposure Management in Radiation-exposed Medical Staff].

PURPOSE: To investigate the actual condition of the crystalline lens equivalent dose and effective dose according to the type of job and the type of duties in a medical institution. We also sought to clarify effective exposure reduction strategies. METHODS: Equivalent crystalline lens doses, effective doses, job type, and duties for 8656 persons · year were obtained from 17 medical facilities. We analyzed the relationship between the effective dose and the crystalline lens equivalent dose in uniform exposure control and non-uniform exposure control conditions. Exposure data were obtained for 13 unique job types and duties. RESULTS: The ratio of the lens equivalent dose to the effective dose of non-uniform exposure managers was 2 to 6 times and varied depending on the occupation. The percentage of persons whose annual lens equivalent dose exceeded 20 mSv was 4.75% for medical doctors, 1.17% for nurses, and 0.24% for radiological technologists. Highly exposed tasks included doctors in cardiology and gastroenterology performing angiography and endoscopy, nurses in endoscopy, and radiological technologists in radiography and CT examinations. CONCLUSION: Thorough unequal exposure control for operations with high crystalline lens exposure, radiation protection education, and effective use of proper personal protective equipment such as the use of radiation protection glasses may reduce lens exposure levels.

Angular dependence of shielding effect of radiation protective eyewear for radiation protection of crystalline lens.

Radiation protective (RP) eyewear effectively protects crystalline lenses from radiation exposure. A drawback of RP eyewear is the angular dependence of the shielding effect, which results from the design of the eyewear. In this study, 21 models of RP eyewear with different designs and lead equivalences were assessed. Each piece of RP eyewear was hung on a Styrofoam phantom that imitated the head, and a 0.125-cc ionization chamber dosimeter was placed at the position of the crystalline lens. The differences in angular dependence of the shielding effect were evaluated by changing the irradiation angle, and parameters that improved the angular dependence of the shielding effect-sufficient lead equivalence, large coverage design, and minimum gap between the crystalline lens and the RP eyewear-were identified. Thus, the findings highlight the importance of selecting RP eyewear according to the angular distribution and the nature of radiation exposure in the workplace for radiation workers.

Electrochemical assay for deoxyribonuclease I activity.

A thiolated oligonucleotide having three ferrocenes was immobilized on a gold electrode through the sulfur-gold linkage. This electrode showed a current response based on the redox reaction of the ferrocene moieties and this response was decreased after treatment with deoxyribonuclease I (DNase I), suggesting the disappearance of the ferrocene moieties on the electrode by the DNase I digestion. A linear correlation between i(0) and i, which are current peaks before and after DNase I treatment, respectively, was observed and this slope was decreased with increase in the amount of DNase I. No current decrease was observed in the presence of EDTA or RNase A instead of DNase I. These results suggested that the current decrease responded specifically to the amount of DNase I and this electrode could be used for an electrochemical DNase I assay. Under the optimum conditions of DNase I digestion at 37 degrees C for 30 min, a quantitative analysis could be achieved in the range of 10(-4)-10(-2)units/microl of DNase I.

Reliable ferrocenyloligonucleotide-immobilized electrodes and their application to electrochemical DNase I assay.

A ferrocenyloligonucleotide (FcODN) having contiguous cytosine bases was immobilized effectively and reproducibly on a gold electrode furnished with a self-assembled monolayer (SAM) having an N-hydroxysuccinimide-activated carboxylic acid. The resulting electrode was used as a sensor chip in DNase I assay. Thus, the current response of the modified electrode decreased upon addition of DNase I, demonstrating that the phosphodiester bonds of FcODN were cleaved. The DNase I activity assessed by Deltai defined as (i0-i)/i0, where i0 and i represent the current before and after DNase I treatment, respectively, was found to be reproducible with a standard deviation not greater than 9%. The DNase I can be quantitated in the range of 10(-5) to 10(-3) units microL(-1) with a detection limit of 10(-5) units microL(-1) with this sensor chip. The current signal of the FcODN electrode was stable to storage in Biopak water up to 16 days with a 30% signal decrease over this period. DNase I activity in human sera was also determined successfully with this sensor chip.

Electrochemical detection of DNase I activity.

DNase I in one microl of the water could quantitate electrochemically with the detection limit of 0.01 units (ca. 20 pg) by using the ferrocenyl oligonucleotide-immobilized electrode prepared by thiolated oligonucleotide and ferrocenyl carbodiimide as a simple labeling reagent of redox unit.

Identification of phosphodiesterase-1 and 5 dual inhibitors by a ligand-based virtual screening optimized for lead evolution.

We identified new lead candidates which showed potent dual inhibition against phosphodiesterase-1 and 5 by a ligand-based virtual screening optimized for lead evolution. This virtual screening method, consisting of classification and regression tree analysis using 168 2-center pharmacophore descriptors and 12 macroscopic descriptors, demonstrated a high predictive ability for bioactivity of new chemical compounds. The obtained lead candidates were structurally diverse, although only the structure-activity relationship data of hydroxamic acid derivatives were used to configure the prediction model for the virtual screening.

Discovery of hydroxamic acid analogs as dual inhibitors of phosphodiesterase-1 and -5.

HTS and the following synthesis of a series of the compounds led us to the discovery of hydroxamic acid analogs as potent dual inhibitors of phosphodiesterase (PDE)-1 and 5. These compounds have highly related structure and deviation of the structure usually resulted in reduced potency. This result can be used to design other molecules that may be utilized for the therapy of cardiovascular symptoms that relates to cGMP level.