Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Utility of a Systematic Approach to Selecting Candidate Prodrugs: A Case Study Using Candesartan Ester Analogues.

Development of prodrugs is a useful strategy to overcome some disadvantages of candidate drugs. Recently, we established a systematic approach to selecting appropriate prodrugs, and validated the utility of this approach using oseltamivir analogues. In this study, the utility of the approach was further examined using candesartan cilexetil and 20 kinds of its analogues having various types of side chain as model compounds. Log D values of analogues (2.5 to 4.7) were higher than that of candesartan (1.0), their active metabolite, and the results were reasonable for the purpose of improving permeability of candesartan. The analogues tended to be more soluble in artificial intestinal fluids than in artificial gastric fluid, owing to their acidic physicochemical characteristics. Their membrane permeabilities were not correlated with log D values, which can be attributed to the metabolism in Caco-2 cells used in this system. In human hepatocytes and enterocytes, 11 out of the 20 analogues were immediately hydrolyzed to candesartan, and species differences were observed in the hydrolysis efficiency. This study confirmed the utility of the systematic approach for selection of appropriate prodrugs that could be proceeded to in vivo pharmacokinetics study, with selection of suitable experimental animals.

A cysteine trapping assay for risk assessment of reactive acyl CoA metabolites.

Some drugs with carboxylic acid moieties can potentially cause rare but severe hepatotoxicity. The reactive chemical species generated by drug metabolism are thought to be one reason for this event. Although the phase II conjugation metabolism of carboxylic acids generally renders a compound more polar and inactive, it is also responsible for the formation of reactive metabolites.This study aimed to provide a new approach towards the risk assessment of carboxylic acids in the aspect of reactive acyl CoA metabolites.Although acyl CoA metabolites have been concerned, it is difficult to detect them because of their instability. We investigated the trapping agents for acyl CoA metabolites. We found that cysteine is a good trapping agent and developed an assay method for the reactivity of acyl CoA metabolites. We evaluated 17 drugs with carboxylic acid moieties, all drugs concerned with hepatotoxicity displayed reactive potential. With consideration of the exposure of each parent drug, the correlation between drug labels and the calculated risk of carboxylic drugs was improved.These evaluations can be conducted without radiochemical reagents or the authentic standards of metabolites. We believe that the method will be beneficial for drug discovery.

The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats.

We investigated the influence of multiple oral administration on the accumulation of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, in rats. It is well known that orally administered dalcetrapib is rapidly hydrolysed to its active form, which has a sulfhydryl group, in the body. The active form then binds covalently to endogenous thiols via mixed disulfide bonds. Following multiple once daily oral administration of 14C-dalcetrapib for seven days to rats, the concentration of radioactivity in the plasma and almost all tissues reached the steady state by day 4. At 24 h after the last dose, there was a relatively high concentration of radioactivity in the mesenteric lymph nodes, liver, adrenal glands and fat. After the last dose to rats, the radioactivity was almost completely recovered in the urine and faeces, indicating that dalcetrapib is not retained in the body, probably due to the reversibility of the disulfide bonds despite being covalent bonds.

Clinical Impact of Worsening Renal Function in Elderly Patients with Acute Decompensated Heart Failure.

Background and Objectives: The clinical significance of worsening renal function (WRF) in elderly patients with acute decompensated heart failure (ADHF) is not completely understood. We compared the clinical conditions between younger and elderly patients with ADHF after the appearance of WRF to establish its prognostic influence. Methods: We included 654 consecutive patients (37% women) admitted for ADHF. We divided the patients into four groups according to their age (<80 years, under-80, n=331; ≥80 years, over-80, n=323) and to their WRF statuses (either WRF or non-WRF group). We defined WRF as an increase in serum creatinine level ≥0.3 mg/dL or ≥150% within 48 hours after hospital arrival (under-80, n=62; over-80, n=75). The primary endpoint was a composite of cardiac events within 1 year. Results: The survival analyses revealed that the WRF group had significantly more cardiac events than the non-WRF group in patients in the over-80 group (log-rank p=0.025), but not in those of the under-80 group (log-rank p=0.50). The patients in the over-80, WRF group presented more significant mean blood pressure (MBP) drops than those in the over-80 non-WRF group (p=0.003). Logistic regression analyses revealed that higher MBP at admission was a significant predictor of WRF. Conclusions: WRF is a predictor of poor outcomes in elderly patients with ADHF.

Systematic Approach for Screening of Prodrugs: Evaluation Using Oseltamivir Analogues as Models.

Prodrug development is a common approach in drug development. In a recent study, we established a systematic strategy for selecting prodrugs with improved membrane permeability or solubility based on log D value, solubility in artificial intestinal fluids, membrane permeability, and metabolic instability. The purpose of this study was to evaluate the utility of this strategy using oseltamivir and 23 kinds of oseltamivir analogues having various types of side chain as well as their active metabolite, oseltamivir acid. Log D values of oseltamivir and analogues (2.0 to 4.9) were higher than that of oseltamivir acid (0.7), supporting the previous development of oseltamivir to improve permeability of oseltamivir acid. Solubilities of analogues in artificial intestinal fluids were over 80%, except the compound with the highest lipophilicity. Positive correlation was observed between membrane permeability and log D values of analogues. In metabolic profiles, species differences in the hydrolysis efficiency were observed depending on analogues. Using our strategy, it was demonstrated that oseltamivir and some analogues are appropriate prodrugs that could be advanced to in vivo pharmacokinetic studies, with selection of suitable animals. This study confirmed the utility of our strategy for narrowing down of candidate compounds to proceed into in vivo study.

Evaluation of the changes in exposure to thiol compounds in chronic kidney disease patients using the PBPK model.

Targeted covalent inhibitors designed to bind covalently to a specific molecular target have recently been a focus of drug development. Among these inhibitors, thiol compounds bind covalently to endogenous thiols in the body through a process involving disulfide bonds. We investigated the predictability of changes in the exposure to captopril, tiopronin, the active form of dalcetrapib and the active metabolite of prasugrel, R-138727, all of which have a sulfhydryl group, in moderate and severe chronic kidney disease (CKD) patients using a constructed PBPK model. The changes in the exposure to captopril, tiopronin and the active form of dalcetrapib under CKD conditions were well predicted. However, the change in exposure to R-138727, which is a secondary metabolite of prasugrel, was overpredicted. Although these thiol compounds covalently bind to endogenous thiols, our study concluded that changes in exposure to these compounds under CKD conditions can probably be predicted, except for compounds with a complicated mechanism whereby the thiol metabolite is generated.

A Novel Systematic Approach for Selection of Prodrugs Designed to Improve Oral Absorption.

To increase the success rate in development of prodrugs, we sought to establish a systematic in vitro method to appropriately select candidate prodrugs. Physicochemical/biopharmaceutical properties of 21 commercially available prodrugs (16 with improved membrane permeability of pharmacologically active metabolites and 5 with improved solubility) and their active metabolites were characterized in terms of solubility in artificial intestinal fluids and membrane permeability using Caco-2 cells. Their in vitro metabolic profiles were also evaluated, using human and animal enterocytes, hepatocytes, and sera. Log D values of prodrugs with improved membrane permeability were higher than those of their active metabolites, whereas those of prodrugs with improved aqueous solubility were lower than those of active metabolites. The prodrugs with improved aqueous solubility were highly soluble in artificial intestinal fluids. All prodrugs were efficiently converted to active metabolites with human matrices, whereas some were not with dog or monkey matrices. This study demonstrated that physicochemical/biopharmaceutical properties could be useful information to facilitate design of prodrugs and for selection of candidate prodrugs. Moreover, the in vitro evaluation of conversion efficiency to active metabolites would be helpful for selecting ideal prodrugs as well as appropriate animals for in vivo PK studies.

Digital zoom is a useful, simple, and cost-effective method of reducing radiation exposure in percutaneous coronary intervention.

Reducing radiation exposure is a very important issue in interventional cardiology techniques such as percutaneous coronary intervention. Although novel techniques to reduce radiation exposure are valuable, we should also reconsider older techniques. Digital zoom has been available in Japan from 2005. Digital zoom enlarges an 8-inch field of view (FOV) by 1.2 times, allowing visualization of a 6.7-inch FOV without FOV switching. We identified 2101 suitable cases of percutaneous intervention (PCI) and divided them into two groups according to the use of digital zoom; 1195 patients were included in the digital zoom group and 906 patients in the conventional group. We collected data regarding the reference air kerma (RAK) and dose-area product (DAP). We calculated RAK and DAP per minute fluoroscope time (RAK/min, DAP/min, respectively). There were intergroup differences in RAK, DAP, RAK/min, and DAP/min (digital zoom group vs conventional group; RAK, 1590 mGy [990-2410] vs 1850 [1220-2720], p < 0.01, RAK/min; 54.7 mGy/min [38.5-73.2] vs 71.2 [51.5-93.0], p < 0.01; DAP, 16,000 cGy × cm2 [10,300-24,400] vs 20,700 [13,400-29,500], p < 0.001; DAP/min, 557 cGy × cm2/min [392-737] vs 782 [571-1010], p < 0.01, respectively). Because of baseline differences between the two groups, we performed propensity score matching. Even after score matching, there were intergroup differences in DAP, DAP/min, RAK, and RAK/min. Furthermore, the least squares method showed that digital zoom is a significant predictor of RAK (ß = 0.14, p < 0.01) and DAP (ß = 0.20, p < 0.01). Digital zoom is an older cost-effective technique that can significantly reduce radiation exposure in PCI.

Proposal of a Parameter for OATP1B1 Inhibition Screening at the Early Drug Discovery Stage.

It is known that potent inhibition of organic-anion-transporting polypeptide (OATP)1B1 increases exposure to statins, leading to severe adverse effects. The aim of this study was to propose a parameter and its criteria in OATP1B1 inhibition assay at the early drug discovery stage to avoid compounds with the risk of statin-related adverse effects. According to drug label information, most compounds classified as "contraindicated" or "should be avoided" when administered concomitantly with statins increased their AUCs more than 4-fold. Generally, R values where R = 1 + plasma unbound fraction (fu) × maximum inhibitor concentration at the inlet to the liver/IC50 are used to evaluate the extent of clinical drug interaction. However, clinical doses and Cmax cannot be determined at the screening stage. Therefore, we estimated the correlations between change in AUC of statins concomitantly administered with OATP1B1 inhibitors and various parameters including fu/IC50. Cyclosporin A, rifampicin, and telaprevir increased the AUC of statins more than 4-fold and fu/IC50 of these compounds was >0.1 L/µmol. On the other hand, fu/IC50 of other compounds was ≤0.03 L/µmol. This study indicates that fu/IC50 is a useful parameter to avoid compounds that seriously affect statin potency through interaction with OATP1B1 at the screening stage.

Correction to: The lactate clearance calculated using serum lactate level 6 h after is an important prognostic predictor after extracorporeal cardiopulmonary resuscitation: a single-center retrospective observational study.

[This corrects the article DOI: 10.1186/s40560-018-0302-z.].

Prediction Accuracy of Mechanism-Based Oral Absorption Model for Dogs.

The purpose of the present study was to evaluate the prediction accuracy of a mechanism-based oral absorption model for the fraction of a dose absorbed (Fa) in dogs, focusing on poorly soluble drugs. As an open mechanism-based model, the gastrointestinal unified theoretical framework was used in this study. The prediction accuracy of the gastrointestinal unified theoretical framework was evaluated using Fa data in dogs (63 data sets for marketed drugs and proprietary compounds). For neutral compounds, Fa was accurately predicted, suggesting that the physiological parameters of dogs were appropriate except for gastrointestinal pH. An extensive literature survey on the small intestinal pH of dogs was then conducted. The result suggested that the pH value ranged between 6.5 and 7.5, with the midst value of 7.0, but there was a great variation among the literature. To confirm the appropriateness of this pH value, the Fa of free acid compounds was predicted by setting the small intestinal pH to 6.5, 7.0, and 7.5. The proportions of compounds with <2-fold error were 57%, 90%, and 76%, respectively. The results of the present study would enable an appropriate use of a mechanism-based model for drug discovery and development.

Ultrasonographic and radiological imaging demonstrating an anomalous origin of the left coronary artery causing acute coronary syndrome in an adolescent.

We report the case of a 13-year-old girl who presented with cardiac collapse secondary to compression of the left main coronary artery (LMCA) between the pulmonary artery and the ascending aorta. In the acute phase, we performed aortography, intra-vascular ultrasound (IVUS), coronary computed tomography angiography (CCTA), transthoracic echocardiography (TTE), and transesophageal echocardiography (TEE). Aortography and CCTA showed that her LMCA was located between her pulmonary artery and the ascending aorta. IVUS and TEE showed that her LMCA was narrowed owing to compression by both great vessels during systole with release of the pressure during diastole. TTE and TEE showed that the left coronary artery flow was faster in the systole than that observed in the diastole. She was initially treated at our hospital but was transferred to another hospital for an unroofing operation. This was a rare case of a patient presenting with a coronary artery anomaly causing cardiac collapse. We conclude that her LMCA stenosis secondary to compression and narrowing of the great vessels led to her cardiac collapse. .

The lactate clearance calculated using serum lactate level 6 h after is an important prognostic predictor after extracorporeal cardiopulmonary resuscitation: a single-center retrospective observational study.

BACKGROUND: Serum lactate level can predict clinical outcomes in some critical cases. In the clinical setting, we noted that patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) and with poor serum lactate improvement often do not recover from cardiopulmonary arrest. Therefore, we investigated the association between lactate clearance and in-hospital mortality in cardiac arrest patients undergoing ECPR. METHODS: Serum lactate levels were measured on admission and every hour after starting ECPR. Lactate clearance [(lactate at first measurement - lactate 6 h after)/lactate at first measurement × 100] was calculated 6 h after first serum lactate measurement. All patients who underwent ECPR were registered retrospectively using opt-out in our outpatient's segment. RESULT: In this retrospective study, 64 cases were evaluated, and they were classified into two groups according to lactate clearance: high-clearance group, > 65%; low-clearance group, ≤ 65%. Surviving discharge rate of high-clearance group (12 cases, 63%) is significantly higher than that of low-clearance group (11 cases, 24%) (p < 0.01). Considering other confounders, lactate clearance was an independent predictor for in-hospital mortality (odds ratio, 7.10; 95% confidence interval, 1.71-29.5; p < 0.01). Both net reclassification improvement (0.64, p < 0.01) and integrated reclassification improvement (0.12, p < 0.01) show that adding lactate clearance on established risk factors improved the predictability of in-hospital mortality. CONCLUSION: In our study, lactate clearance calculated through arterial blood gas analysis 6 h after ECPR was one of the most important predictors of in-hospital mortality in patients treated with ECPR after cardiac arrest.