Discovery of a novel series of medium-sized cyclic enteropeptidase inhibitors.

Enteropeptidase is located in the duodenum that involved in intestinal protein digestion. We have reported enteropeptidase inhibitors with low systemic exposure. The aim of this study was to discover novel enteropeptidase inhibitors showing more potent in vivo efficacy while retaining low systemic exposure. Inhibitory mechanism-based drug design led us to cyclize ester 2 to medium-sized lactones, showing potent enteropeptidase inhibitory activity and improving the ester stability, thus increasing fecal protein output in vivo. Optimization on the linker between two benzene rings resulted in discovery of ether lactone 6b, exhibiting further enhanced enteropeptidase inhibitory activity and long duration of inhibitory state. Oral administration of 6b in mice significantly elevated fecal protein output compared with the lead 2. In addition, 6b showed low systemic exposure along with low intestinal absorption. Furthermore, we identified the 10-membered lactonization method for scale-up synthesis of 6b, which does not require high-dilution conditions.

Temperature difference between jugular bulb and pulmonary artery is associated with neurological outcome in patients with severe traumatic brain injury: A post hoc analysis of a brain hypothermia study.

BACKGROUND: The purpose of this study was to examine whether the temperature difference between the jugular bulb and pulmonary artery (ΔTjb-pa) is associated with the neurological outcome of patients with severe traumatic brain injury (TBI). METHODS: We conducted a post hoc analysis of a multicenter randomized controlled trial of mild therapeutic hypothermia (TH, 32.0-34.0°C) or fever control (FC, 35.5-37.0°C) for the patients with severe TBI. ΔTjb-pa averaged every 12 h and the variation in ΔTjb-pa were compared between patients with favorable (n = 39) and unfavorable (n = 37) neurological outcomes. These values were also compared in the TH and FC subgroups. RESULTS: The average ΔTjb-pa values in patients with favorable and unfavorable outcomes were 0.24 ± 0.23 and 0.06 ± 0.36°C, respectively (P < 0.001). ΔTjb-pa trended significantly higher in the favorable outcome patients than in the unfavorable outcome patients throughout the 120 h after onset of severe TBI (P < 0.001). The variation in ΔTjb-pa from 0 to 72 h was significantly lower in the favorable outcome patients than in the unfavorable outcome patients (0.8 ± 0.8 vs 1.8 ± 2.5°C, respectively, P = 0.013). From 72 to 120 h, there was no significant difference in the variation in ΔTjb-pa. Significant differences between patients with favorable and unfavorable outcomes in ΔTjb-pa and the variation in ΔTjb-pa were similar in the TH subgroup, but not evident in the FC subgroup. CONCLUSIONS: A reduction in ΔTjb-pa and greater variation in ΔTjb-pa were associated with an unfavorable outcome in patients with severe TBI, especially those treated with TH. When treating severe TBI patients, it is important to understand that there will be differences in temperature reflecting the brain environment and the systemic temperature, depending on the severity and outcome of TBI during TH.

Benefits of Hypothermia for Young Patients with Acute Subdural Hematoma: A Computed Tomography Analysis of the Brain Hypothermia Study.

Therapeutic hypothermia for severe traumatic brain injury (TBI) has been repeatedly studied, but no past studies have assessed the detailed head computed tomography (CT) findings. We sought to investigate individual CT findings of severe TBI patients treated with targeted temperature management utilizing the head CT database obtained from the Brain Hypothermia study. Enrolled patients underwent either mild therapeutic hypothermia (32.0°C-34.0°C) or fever control (35.5°C-37.0°C). We assessed individual head CT images on arrival and after rewarming and investigated the correlations with outcomes. The initial CT data were available for 125 patients (hypothermia group = 80, fever control group = 45). Baseline characteristics and CT findings, such as hematoma thickness and midline shift, were similar in all aspects between the two groups. The favorable outcomes in the hypothermia and fever control groups were 38 (47.5%) and 24 (53.3%; p = 0.53) for all 125 patients, respectively; 21 (46.7%) vs. 10 (38.5%; p = 0.50) for 71 patients with acute subdural hematoma (SDH), respectively; and 12 (75.0%) vs. 4 (36.4%; p = 0.045) in 27 young adults (≤50 years) with acute SDH, respectively. There was a trend toward favorable outcomes for earlier time to reach 35.5°C (190 vs. 377 min, p = 0.052) and surgery (155 vs. 180 min, p = 0.096) in young patients with acute SDH. The second CT image revealed progression of the brain injury. This study demonstrated the potential benefits of early hypothermia in young patients with acute SDH, despite no difference in CT findings between the two groups. However, the small number of cases involved hindered the drawing of definitive conclusions. Future studies are warranted to validate the results.

Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity.

To discover a novel series of potent inhibitors of enteropeptidase, a membrane-bound serine protease localized to the duodenal brush border, 4-guanidinobenzoate derivatives were evaluated with minimal systemic exposure. The 1c docking model enabled the installation of an additional carboxylic acid moiety to obtain an extra interaction with enteropeptidase, yielding 2a. The oral administration of 2a significantly elevated the fecal protein output, a pharmacodynamic marker, in diet-induced obese (DIO) mice, whereas subcutaneous administration did not change this parameter. Thus, systemic exposure of 2a was not required for its pharmacological effects. Further optimization focusing on the in vitro IC50 value and T1/2, an indicator of dissociation time, followed by enhanced in vivo pharmacological activity based on the ester stability of the compounds, revealed two series of potent enteropeptidase inhibitors, a dihydrobenzofuran analogue ((S)-5b, SCO-792) and phenylisoxazoline (6b), which exhibited potent anti-obesity effects despite their low systemic exposure following their oral administration to DIO rats.

High early phase hemoglobin level is associated with favorable neurological outcome in patients with severe traumatic brain injury.

BACKGROUND: The appropriate hemoglobin (Hb) level threshold for the early phase (i.e. from Emergency Department to ICU admission) in patients with severe traumatic brain injury (TBI) is still unknown. Therefore, we aimed to examine the association between Hb levels during the early phase and neurological outcomes in patients with severe TBI using data from the Brain Hypothermia (B-HYPO) Study Group. METHODS: We performed a post-hoc analysis of the B-HYPO study (a prospective, multicenter, randomized controlled trial on patients with severe TBI who received either mild therapeutic hypothermia [MTH; 32.0 °C-34.0 °C] or fever control [35.5 °C-37.0 °C]). We calculated Hb levels during early phase by the formula: (admission Hb + Hb on day 1) / 2. The primary outcome was the association between during early phase Hb levels and 6-month neurological outcome after the TBI based on the Glasgow Outcome Scale scores (a measure of functional recovery defined as moderate disability or good recovery). RESULTS: We reviewed data from 130 patients and found favorable neurological outcomes in 48.5% of them. We found significant differences between the favorable and unfavorable neurological outcome groups in terms of their Hb levels on admission and on day 1. But, we found no Hb level differences after day 3 (including 1 day after rewarming). Our multivariable analysis showed that Hb levels during early phase were significantly associated with favorable neurological outcomes (odds ratio, 1.387; 95% confidence interval, 1.057-1.858; P = 0.018). CONCLUSIONS: High early phase Hb levels are associated with favorable neurological outcomes after severe TBI.

Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2-Carbamoylphenyl Piperidine Moiety.

GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic ß-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular π-π stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.

Precision and Safety of an Intravascular Temperature Management System for Postcardiac Arrest Syndrome Patients: A Multicenter Clinical Trial (COOL-ARREST JP).

Rapid induction and maintaining a target temperature of 32.0-36.0°C within a narrow range for <24 hours are essential, but those are very hard to perform in postcardiac arrest syndrome (PCAS) patients. We investigated the usability of an intravascular temperature management (IVTM) system with neurolept-anesthesia (NLA; droperidol and fentanyl). Single-arm, prospective multicenter trial was carried out in the seven university and the three affiliated hospitals. In the 24 comatose PCAS patients, the target temperature (33.0°C) was rapidly induced and maintained for 24 hours using an IVTM system with NLA. The rewarming speed was 0.1°C/h until 36.5°C and was maintained for 24 hours. The primary end point was the ability to achieve ≤34.0°C for <3 hours after starting cooling, and the secondary end points were the cooling rate, deviation from the target temperature, and adverse events. Cerebral Performance Category (CPC) score at 14 days was also evaluated. Statistical analyses were performed by SPSS software, using the intention-to-treat data sets. The target temperature of ≤34.0°C was reached by 45 minutes (35-73 minutes) and was within 3 hours in all patients. The cooling rate from 36.4°C to 33.0°C was 2.7°C/h (2.4-3.6°C/h). The temperature of 33.1°C (33.1-33.1°C) and 36.7°C (36.6-36.9°C) for 24 hours each was held during the maintenance and the after rewarming phases, respectively. Temperature deviations >0.2°C from 33.0°C in the maintenance phase occurred once each in two patients. The favorable neurological outcomes (CPC1, 2) were relatively good (50%). Five patients experienced serious adverse events; none was device related. We rapidly achieved therapeutic hypothermia within a narrow temperature range without major complications using the IVTM system with NLA in PCAS patients.

Post-hepatectomy tolvaptan-induced hypernatremia in a hepatocellular carcinoma patient with cirrhosis: a case report.

BACKGROUND: Tolvaptan is used in Japan to reduce fluid retention caused by cirrhosis. However, hypernatremia is one of the most important side effects. This report is the first case report of a patient who developed hypernatremia after tolvaptan administration in the early stages following hepatectomy. CASE PRESENTATION: A female patient in her 60s, who was admitted to the psychiatric department of a different hospital for bipolar disorder, developed hepatocellular carcinoma with cirrhosis. She was transferred to our hospital, and hepatectomy was performed in October 2019, after which pleural effusion and severe edema due to fluid retention were evident. Thus, the patient was started on tolvaptan (7.5 mg/day) from postoperative day (POD) 1. The patient began to experience disturbance of consciousness after POD 4. On the fifth day, the serum sodium (Na) level increased to 174 mEq/L, and hypernatremia was diagnosed. The Na level gradually improved with fluid infusion therapy, dropping to preoperative levels on the ninth day; her consciousness also gradually improved. CONCLUSIONS: Tolvaptan administration must be performed under strictly controlled conditions, followed by careful observation during the early postoperative period, when the patient's physical status is unstable.

Prognostic Significance of the Difference Between Mixed and Jugular Venous Oxygen Saturation After Severe Traumatic Brain Injury: A Post Hoc Analysis of the Brain Hypothermia Study.

BACKGROUND: In patients postcardiac arrest, it has been reported that the small value of the difference between mixed venous oxygen saturation (Svo2) and jugular venous oxygen saturation (Sjvo2) is associated with poor neurologic outcome. However, the importance of the difference between mixed venous oxygen saturation and jugular venous oxygen saturation (ΔSo2 [v - jv]) remains unknown in severe traumatic brain injury (TBI). The aim of this study was to examine whether ΔSo2 (v - jv) is associated with neurologic outcome and mortality in patients with severe TBI. METHODS: We conducted post hoc analyses of the Brain Hypothermia Study, a multicenter randomized controlled trial of mild therapeutic hypothermia for the treatment of severe TBI. The value of ΔSo2(v - jv) on day 1 and day 3 was compared between survivors (n = 65) and nonsurvivors (n = 25) or between patients with favorable (n = 47) and unfavorable (n = 43) neurologic outcomes. RESULTS: The reduction in ΔSo2 (v - jv) on day 3 was -2.0% (range, -6.9% to 6.5%) in the nonsurvivor group and 6.3% (range, -2.5% to 16.7%) in the survivor group. The difference was statistically significant (P = 0.03). The same tendencies were observed in the nonsurvivor group on day 1 and in the unfavorable neurologic outcome group on day 1 and day 3, but the difference was not significant. CONCLUSIONS: The reduction in ΔSo2(v - jv) on day 3 was associated with high mortality in patients with severe TBI.

SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity.

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

SCO-792, an enteropeptidase inhibitor, improves disease status of diabetes and obesity in mice.

AIMS: Enteropeptidase is a serine protease localized on the duodenal brush border that catalyzes the conversion of inactive trypsinogen into active trypsin, thereby regulating protein breakdown in the gut. We evaluated the effects of SCO-792, a novel enteropeptidase inhibitor, in mice. MATERIALS AND METHODS: In vivo inhibition of enteropeptidase was evaluated via an oral protein challenge. Pharmacological effects were evaluated in normal mice, in diet-induced obese (DIO) mice and in obese and diabetic ob/ob mice. RESULTS: A single oral administration of SCO-792 inhibited plasma branched-chain amino acids (BCAAs) in an oral protein challenge test in mice, indicating in vivo inhibition of enteropeptidase. Repeated treatment with SCO-792 induced reduction in food intake and decrease in body weight in DIO and ob/ob mice. Plasma FGF21 levels were increased in SCO-792-treated DIO mice, an observation that was probably independent of reduction in food intake. Hyperglycaemia was markedly improved in SCO-792-treated ob/ob mice. A hyperinsulinaemic-euglycaemic clamp study revealed improved muscle insulin sensitivity in SCO-792-treated ob/ob mice. SCO-792 also improved plasma and liver lipid profiles and decreased plasma alanine transaminase, suggesting a potential treatment for liver diseases. Dietary supplementation with essential amino acids attenuated the effect of SCO-792 on reduction in food intake and decrease in body weight in normal mice, suggesting a pivotal role for enteropeptidase in these biological phenomena. CONCLUSIONS: SCO-792 inhibited enteropeptidase in vivo, reduced food intake, decreased body weight, increased insulin sensitivity, improved glucose and lipid control, and ameliorated liver parameters in mouse models with obesity and/or diabetes. SCO-792 may exhibit similar effects in patients.

Mild decrease in heart rate during early phase of targeted temperature management following tachycardia on admission is associated with unfavorable neurological outcomes after severe traumatic brain injury: a post hoc analysis of a multicenter randomized controlled trial.

BACKGROUND: The association between isolated admission heart rate (HR) and prognosis has been discussed, but not that between gross HR change and neurological outcome in patients with severe traumatic brain injury (TBI). In the acute phase of severe TBI, HR is influenced by several factors (e.g., pain, sympathetic activation, hypovolemia, fever, body temperature). Therefore, admission HR and gross HR change should be examined in patients with TBI treated with a well-designed protocol, such as was done in the Brain Hypothermia (B-HYPO) Study. METHODS: This was a post hoc analysis of the B-HYPO Study, which was conducted as a prospective, multicenter, randomized controlled trial in patients with severe TBI receiving mild therapeutic hypothermia (MTH; 32.0 °C-34.0 °C) or fever control (35.5 °C-37.0 °C) in Japan. Patients with MTH were examined, and HR change (%HR) in the early MTH phase was calculated as follows: [admission HR - HR at day 1]/admission HR × 100. Patients were divided into six groups, using admission HR (< 80, 80-99, ≤ 100) and median of %HR; i.e., group (Admission HR < 80 and %HR ≥ 18.6); group (Admission HR < 80 and %HR < 18.6); group (Admission HR 80-99 and %HR ≥ 18.6); group (Admission HR 80-99 and %HR < 18.6); group (Admission HR ≥100 and %HR ≥ 18.6); and group (Admission HR ≥100 and %HR < 18.6). The primary outcome was an adjusted predicted probability of unfavorable neurological outcome at 6 months after TBI according to Glasgow Outcome Scale score, which is a measure of functional recovery and defined as severe disability, persistent vegetative state, and death. RESULTS: Overall, 79 patients with MTH (52.7% of the original trial) were examined; among these, unfavorable neurological outcomes were observed in 53.2%. Among all the groups, group (Admission HR ≥100 and %HR < 18.6) exhibited the highest proportion of unfavorable outcomes, and 82.3% of patients had an adjusted predicted probability of unfavorable outcomes, whereas those in group (Admission HR < 80 and %HR ≥ 18.6) developed only 22.8% (p = 0.04). CONCLUSIONS: Mild HR decrease during the early phase of targeted temperature management following tachycardia at admission can be associated with unfavorable neurological outcomes after severe TBI.

Slow rewarming improved the neurological outcomes of prolonged mild therapeutic hypothermia in patients with severe traumatic brain injury and an evacuated hematoma.

Mild therapeutic hypothermia (MTH) is expected to improve the neurological outcomes of patients with severe traumatic brain injury (TBI). However, there are no standard protocols for managing the temperature of patients with severe TBI in order to improve their neurological outcomes. We conducted a post hoc analysis of the B-HYPO study, a randomized controlled trial of MTH in patients with TBI in Japan. We evaluated the impact of MTH methods on neurological outcomes. Ninety-seven patients who received MTH were included in the present analyses. The neurological outcomes were compared among subgroups of patients divided by cutoff values for the induction, maintenance, and rewarming times of MTH in all patients, in patients with diffuse injury, and in patients with an evacuated hematoma. The proportion of patients with a good neurological outcome was significantly different between patients with an evacuated hematoma divided into subgroups by the cutoff value of rewarming time of 48 h (>48 h vs. ≤ 48 h: 65% vs. 22%; odds ratio: 6.61; 95% confidence interval: 1.13-38.7, P = 0.0498). Slow rewarming for >48 h might improve the neurological outcomes of prolonged MTH in patients with TBI and an evacuated hematoma. Further studies are needed to investigate the optimal rewarming protocol in patients with TBI.

Therapeutic hypothermia in patients with coagulopathy following severe traumatic brain injury.

BACKGROUND: Coagulopathy in traumatic brain injury (TBI) has been associated with poor neurological outcomes and higher in-hospital mortality. In general principle of trauma management, hypothermia should be prevented as it directly worsens coagulopathy. Therefore, we examined the safety of mild therapeutic hypothermia (MTH) in patients with coagulopathy following severe TBI. METHODS: We re-evaluated the brain hypothermia (B-HYPO) study data based on coagulopathy and compared the Glasgow Outcome Scale scores and survival rates at 6 months using per protocol analyses. Coagulopathy was defined as an activated partial thromboplastin time (APTT) > 60 s and/or fibrin/fibrinogen degradation product levels (FDP) > 90 µg/mL on admission. Baseline characteristics, coagulation parameters, and outcomes were compared between the control and MTH groups with or without coagulopathy. RESULTS: In patients with coagulopathy, 12 patients were allocated to the control group (35.5-37.0 °C) and 20 patients to the MTH group (32-34 °C). In patients without coagulopathy, 28 were allocated to the control group and 59 patients were allocated to the MTH group. In patients with coagulopathy, favorable neurological outcomes and survival rates were comparable between the control and MTH groups (33.3% vs. 35.0%, P = 1.00; 50.0% vs. 60.0%, P = 0.72) with no difference in complication rates. On admission, no significant differences in APTT or FDP levels were observed between the two groups; however, APTT was significantly prolonged in the MTH group compared to the control group on day 3. DISCUSSION: Based on our study, MTH did not seem to negatively affect the outcomes in patients with coagulopathy following severe TBI on admission; therefore, the present study indicates that MTH may be applicable even in patients with severe TBI and coagulopathy. CONCLUSIONS: Our study suggests that in comparison to control, MTH does not worsen the outcome of patients with coagulopathy following severe TBI. TRIAL REGISTRATION: UMIN-CTR, No. C000000231 , Registered 13 September 2005.

Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ-5 Desaturase (D5D) Inhibitors.

The discovery and optimization of Δ-5 desaturase (D5D) inhibitors are described. Investigation of the 1,3-oxazolidin-2-one scaffold was inspired by a pharmacophore model constructed from the common features of several hit compounds, resulting in the identification of 3,5-diphenyl-1,3-oxazolidin-2-one 5h as a novel lead showing potent in vitro activity. Subsequent optimization focused on the modification of two metabolic sites, which provided (4S,5S)-5i, a derivative with improved metabolic stability. Moreover, adding a substituent into the upper phenyl moiety further enhanced the intrinsic activity, which led to the discovery of 5-[(4S,5S)-5-(4fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]benzene-1,3-dicarbonitrile (4S,5S)-5n, endowed with excellent D5D binding affinity, cellular activity, and high oral bioavailability in a mouse. It exhibited robust in vivo hepatic arachidonic acid/dihomo-γ-linolenic acid ratio reduction (a target engagement marker) in an atherosclerosis mouse model. Finally, an asymmetric synthetic procedure for this compound was established.

Discovery of novel 5-oxa-2,6-diazaspiro[3.4]oct-6-ene derivatives as potent, selective, and orally available somatostatin receptor subtype 5 (SSTR5) antagonists for treatment of type 2 diabetes mellitus.

Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N-benzyl azetidine derivatives 1 and 2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of 1 to enhance SSTR5 antagonistic activity by the combination of the substituents at the 3-position of the isoxazoline. Incorporation of a carboxyl group at the 4-position of the benzene ring resulted in a significant enhancement in potency, however, the 4-benzoic acid derivative 10c exhibited moderate human ether-a-go-go related gene (hERG) inhibitory activity. A subsequent optimization study revealed that replacement of the 4-benzoic acid with an isonipecotic acid dramatically reduced hERG inhibition (5.6% inhibition at 30µM) by eliminating π-related interaction with hERG K+ channel, which resulted in the identification of 1-(2-((2,6-diethoxy-4'-fluorobiphenyl-4-yl)methyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)piperidin-4-carboxylic acid 25a (hSSTR5/mSSTR5 IC50=9.6/57nM). Oral administration of 25a in high-fat diet fed C57BL/6J mice augmented insulin secretion in a glucose-dependent manner and lowered blood glucose concentration.

Discovery of novel somatostatin receptor subtype 5 (SSTR5) antagonists: Pharmacological studies and design to improve pharmacokinetic profiles and human Ether-a-go-go-related gene (hERG) inhibition.

Somatostatin (SST) is a peptide hormone comprising 14 or 28 amino acids that inhibits endocrine and exocrine secretion via five distinct G-protein-coupled receptors (SSTR1-5). SSTR5 has an important role in inhibiting the secretion of pancreatic and gastrointestinal hormones (e.g., insulin, GLP-1, PYY) through the binding of SSTs; hence, SSTR5 antagonists are expected to be novel anti-diabetic drugs. In the course of our lead generation program of SSTR5 antagonists, we have discovered a novel spiroazetidine derivative 3a. However, pharmacological evaluation of 3a revealed that it had to be administered at a high dose (100mg/kg) to show a persistent glucose-lowering effect in an oral glucose tolerance test (OGTT). We therefore initiated an optimization study based on 3a aimed at improving the antagonistic activity and mean residence time (MRT), resulting in the identification of 2-cyclopropyl-5-methoxybiphenyl derivative 3k. However, 3k did not show a sufficient persistent glucose-lowering effect in an OGTT; moreover, hERG inhibition was observed. Hence, further optimization study of the biphenyl moiety of compound 3k, focused on improving the pharmacokinetic (PK) profile and hERG inhibition, was conducted. Consequently, the introduction of a chlorine atom at the 6-position on the biphenyl moiety addressed a putative metabolic soft spot and increased the dihedral angle of the biphenyl moiety, leading to the discovery of 3p with an improved PK profile and hERG inhibition. Furthermore, 3p successfully exhibited a persistent glucose-lowering effect in an OGTT at a dose of 3mg/kg.

Early-Stage Hyperoxia Is Associated with Favorable Neurological Outcomes and Survival after Severe Traumatic Brain Injury: A Post-Hoc Analysis of the Brain Hypothermia Study.

The effects of hyperoxia on the neurological outcomes of patients with severe traumatic brain injury (TBI) are still controversial. We examined whether the partial pressure of arterial oxygen (PaO2) and hyperoxia were associated with neurological outcomes and survival by conducting post-hoc analyses of the Brain Hypothermia (B-HYPO) study, a multi-center randomized controlled trial of mild therapeutic hypothermia for severe TBI. The differences in PaO2 and PaO2/fraction of inspiratory oxygen (P/F) ratio on the 1st day of admission were compared between patients with favorable (n = 64) and unfavorable (n = 65) neurological outcomes and between survivors (n = 90) and deceased patients (n = 39). PaO2 and the P/F ratio were significantly greater in patients with favorable outcomes than in patients with unfavorable neurological outcomes (PaO2: 252 ± 122 vs. 202 ± 87 mm Hg, respectively, p = 0.008; P/F ratio: 455 ± 171 vs. 389 ± 155, respectively, p = 0.022) and in survivors than in deceased patients (PaO2: 242 ± 117 vs. 193 ± 75 mm Hg, respectively, p = 0.005; P/F ratio: 445 ± 171 vs. 370 ± 141, respectively, p = 0.018). Similar tendencies were observed in subgroup analyses in patients with fever control and therapeutic hypothermia, and in patients with an evacuated mass or other lesions (unevacuated lesions). PaO2 was independently associated with survival (odds ratio 1.008, p = 0.037). These results suggested that early-stage hyperoxia might be associated with favorable neurological outcomes and survival following severe TBI.

Plasma Potassium Concentration on Admission Correlates with Neurologic Outcome in Traumatic Brain Injury Patients Treated with Targeted Temperature Management: A Post Hoc Analysis of a Multicenter Randomized Controlled Trial.

BACKGROUND: Recent studies have focused on the association between plasma electrolytes, particularly potassium level and neurologic outcomes in patients with traumatic brain injury (TBI). We hypothesized that potassium level on admission is an indicator for initiation of targeted temperature management in patients with severe TBI. METHODS: We re-evaluated the Brain Hypothermia Study data based on the potassium levels on admission (i.e., hypokalemia [<3.5 mEq/L] or normokalemia [3.5-5 mEq/L]) and compared these values and Glasgow Outcome Scale scores at 6 months by per protocol analysis. Consequently, 135 patients were enrolled. Finally, groups 50 and 23 patients with hypokalemia and 34 and 23 patients with normokalemia were allocated to mild therapeutic hypothermia (MTH) and fever control groups, respectively. Baseline characteristics, complication rates, and favorable neurologic outcome rates were compared between the two groups. RESULTS: In the normokalemia patients, fever control management was associated with a significant increase in favorable neurologic outcome compared with those in the MTH group (68.2% vs. 35.3%; P = 0.03). The complication rate was significantly higher in the MTH group than in the fever control group for patients with normokalemia (23.4% vs. 0%; P = 0.03). Conversely, hypokalemia patients in the MTH group revealed relatively better favorable neurologic outcomes compared with those in the fever control group (52.0% vs. 39.1%; P = 0.33). CONCLUSIONS: The initial potassium level may be an indicator in determining appropriate targeted temperature management for patients with TBI. Fever control may be considered instead of MTH for normokalemia patients with TBI on admission.