Evaluation of artificial intelligence using time-lapse images of IVF embryos to predict live birth.

RESEARCH QUESTION: Can artificial intelligence (AI) improve the prediction of live births based on embryo images? DESIGN: The AI system was created by using the Attention Branch Network associated with deep learning to predict the probability of live birth from 141,444 images recorded by time-lapse imaging of 470 transferred embryos, of which 91 resulted in live birth and 379 resulted in non-live birth that included implantation failure, biochemical pregnancy and clinical miscarriage. The possibility that the calculated confidence scores of each embryo and the focused areas visualized in each embryo image can help predict subsequent live birth was examined. RESULTS: The AI system for the first time successfully visualized embryo features in focused areas that had potential to distinguish between live and non-live births. No visual feature of embryos were visualized that were associated with live or non-live births, although there were many images in which high-focused areas existed around the zona pellucida. When a cut-off level for the confidence score was set at 0.341, the live birth rate was significantly greater for embryos with a score higher than the cut-off level than for those with a score lower than the cut-off level (P < 0.001). In addition, the live birth rate of embryos with good morphological quality and confidence scores higher than 0.341 was 41.1%. CONCLUSIONS: The authors have created an AI system with a confidence score that is useful for non-invasive selection of embryos that could result in live birth. Further study is necessary to improve selection accuracy.

Trends of fetal chromosome analysis by amniocentesis before and after beginning of noninvasive prenatal testing: A single-center experience in Japan.

AIM: This study is to investigate the role of amniocentesis for prenatal diagnosis before and after the beginning of noninvasive prenatal testing (NIPT) in Japan. METHODS: We performed a retrospective analysis of genetic amniocentesis at mid-trimester (15-20 gestational weeks) for fetal karyotype analysis at Nagoya City University between April 2006 and March 2020. The indications, test results, and the detection rate of fetal abnormal karyotype were compared before (phase 1, P1) and after (phase 2, P2) beginning of NIPT at April 2013. RESULTS: A total of 2458 (P1: 1132, P2: 1326) amniocentesis were enrolled in this study. The most frequent indication was advanced maternal age in both phases (P1: 78.2% %, P2: 81.1%). In P2, 110 patients (8.3%) received amniocentesis after positive or nonreportable NIPT results. Other indications were fetal abnormal findings by ultrasounds (P1: 15.4%, P2: 17.7%), abnormal maternal serum screening results (P1: 8.0%, P2: 10%), previous child with fetal chromosome aberration (P1: 6.5%, P2: 3.5%), and translocation of either partner (P1:1.5%, P2: 2.1%). The detection rate for fetal chromosomal aberrations including all indications was significantly increased in P2 (15.9%, 95% CI 14.0-18.0) as compared to P1 (9.0%, 7.4-10.8). However, if the indication was only advanced maternal age, the positive detection rate kept low in both phases (P1: 5.2%, 3.7-7.1, P2: 4.2%, 2.9-5.9). CONCLUSION: Since the initiation of NIPT, the detection rate of fetal chromosomal abnormalities was higher in this study, suggesting that amniocentesis cannot be strongly recommended for advanced maternal age alone.

Development of a potent and orally active activator of adenosine monophosphate-activated protein kinase (AMPK), ASP4132, as a clinical candidate for the treatment of human cancer.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a key role in maintaining cellular metabolism. AMP or adenosine diphosphate (ADP) levels rise during metabolic stress, such as during nutrient starvation, hypoxia and muscle contraction, and bind to AMPK to induce activity. Recently, activation of AMPK has been considered an attractive therapeutic strategy in the field of human oncology. Structural optimization of lead compound 2, a new type of AMPK activator with potent AMPK activation activity and attractive selective growth inhibition against human cancer cells, improved aqueous solubility, metabolic stability and animal pharmacokinetics (PK) and culminated in the identification of (5-{1-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}-1H-benzimidazol-2-yl)(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)methanone ditosylate, ASP4132 (28). Studies on ASP4132 had advanced to clinical trials for the treatment of cancer.

Novel Indirect AMP-Activated Protein Kinase Activators: Identification of a Second-Generation Clinical Candidate with Improved Physicochemical Properties and Reduced hERG Inhibitory Activity.

This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-({4-[5-({1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.

Discovery of 3,5-Dimethylpyridin-4(1H)-one Derivatives as Activators of AMP-Activated Protein Kinase (AMPK).

Novel 3,5-dimethylpyridin-4(1H)-one scaffold compounds were synthesized and evaluated as AMP-activated protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of compounds showed selective cell growth inhibitory activity against human breast cancer cell lines. By optimizing the lead compound (4a) from our library, 2-[({1'-[(4-fluorophenyl)methyl]-2-methyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl}oxy)methyl]-3,5-dimethylpyridin-4(1H)-one (25) was found to have potent AMPK activating activity. Compound 25 also showed good aqueous solubility while maintaining the unique selectivity in cell growth inhibitory activity.

Combined effect of astaxanthin and squalene on oxidative stress in vivo.

Obesity and diabetes, risk factors for metabolic syndrome, are characterized by oxidative stress and inflammatory responses. Marine biofunctionals, astaxanthin (Ax) and squalene (SQ), were evaluated for their combined effect. Groups of male KK-A (y) mice were fed high fat/sucrose diet for 4 weeks, supplemented with either 0.1 %Ax, 2 %SQ or 0.1 %Ax + 2 %SQ. In comparison to control, Sod was elevated in only Ax + SQ. However, Gpx was highest in Ax + SQ, indicating the combined antioxidant effect of Ax and SQ. This was supported by elevated mRNA expression of Sod1 and Gpx1. Except adiponectin (elevated in Ax and Ax + SQ), expression of other inflammatory markers was not altered. Blood glucose levels were decreased in SQ and Ax + SQ while liver triglycerides decreased in SQ group. This is the first in vivo study demonstrating combined effects of Ax and SQ resulting in antioxidant effects and modulation of glucose/triglyceride levels. This study highlights the benefit of utilizing Ax and SQ together for management of obesity/diabetes.

Immediate effect of spinal magnetic stimulation on camptocormia in Parkinson's disease.

OBJECTIVES: Spinal cord stimulation is a potential therapeutic option for the treatment of Parkinson's disease (PD)-associated symptoms. Repetitive trans-spinal magnetic stimulation (rTSMS) is a non-invasive and safe alternative for stimulation of spinal pathways that has not been studied for therapeutic efficacy in PD. We assessed the benefits of rTSMS on camptocormia, an often treatment-resistant postural abnormality observed in PD patients. METHODS: We compared rTSMS to sham stimulation in PD patients with camptocormia in a single-centre, randomised, single-blind, crossover, placebo-controlled study. PD patients with camptocormia were administered a single trial of rTSMS (a train of 40 stimuli) or sham treatment followed 1 week later by the alternate treatment. Primary outcome measure was thoracolumbar spine flexion angle in the standing position immediately after the trial. RESULTS: Of 320 PD patients examined, 37 had concomitant camptocormia and were randomly assigned to either the rTSMS first group (n=19) or sham first group (n=18). Flexion angle in the standing position decreased by a mean of 10.9° (95% CI 8.1 to 13.65) after rTSMS but remained unchanged after sham stimulation (mean, -0.1°; 95% CI -0.95 to 0.71). The flexion angle while sitting (secondary outcome) decreased by 8.1° (95% CI 5.89 to 10.25) after rTSMS, whereas sham treatment had no significant effect (mean, -0.8°; 95% CI -1.62 to 0.05). CONCLUSIONS: We found an immediate beneficial effect of rTSMS on camptocormia in PD patients. Although the effect was transient, this successful trial justifies further studies to test if repeated rTSMS treatments can induce longer term improvements in camptocormia associated with PD. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000011495.

The effect of early irregular cell division of human embryos on blastocyst euploidy: considerations from the subsequent development of the blastomeres by direct or reverse cleavage.

OBJECTIVE: To investigate whether blastocysts that divide irregularly reduce subsequent blastocyst euploidy. DESIGN: Retrospective study. SETTING: Private clinic. PATIENT(S): A total of 122 blastocysts for which consent for disposal and research use was obtained. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Results of next-generation sequencing analysis of the blastocysts and whether blastomeres by normal or irregular divisions subsequently participated in blastocyst formation or not. RESULT(S): The embryos were classified according to their dynamics until the second cleavage. The blastocyst euploidy rates were 33.3% (19/57) in the normal cleavage (NC) group, 38.3% (18/47) in the direct cleavage (embryos with one cell dividing into 3 cells) (DC) group, and 72.2% (13/18) in the reverse cleavage (RC) (embryos with fused cells once divided) group. The rate of the RC group was significantly higher than that of the NC group. The blastocyst participation rate of the blastomeres were 95.6% in the NC group and 56.5% in that derived from DC of the first cleavage, and 91.7% in that of blastomeres derived from normal division of the second cleavage and 53.6% in that derived from DC of the second cleavage, both of which were significantly lower in the latter. In the RC group, the rates of fused and nonfused blastomeres were 62.1% and 87.5%, respectively, with no significant difference. CONCLUSION(S): The blastomeres generated by DC were often excluded from blastocyst formation, and we speculate that this is one reason why their division does not reduce blastocyst euploidy. The association between RC and euploidy of blastocysts merits further study.

Coulombic aggregations of Mn(III) salen-type complexes and Keggin-type polyoxometalates: isolation of Mn2 single-molecule magnets.

The reaction of Mn(III) salen-type complexes with di- and tetraanionic α-Keggin-type polyoxometalates (POMs) was performed, and three types of Coulombic aggregations containing Mn(III) out-of-plane dimeric units (abbreviated as [Mn(2)](2+)) that are potentially single-molecule magnets (SMMs) with an S(T) = 4 ground state were synthesized: [Mn(2)(5-MeOsaltmen)(2)(acetone)(2)][SW(12)O(40)] (1), [Mn(2)(salen)(2)(H(2)O)(2)](2)[SiW(12)O(40)] (2), and [Mn(5-Brsaltmen)(H(2)O)(acetone)](2)[{Mn(2)(5-Brsaltmen)(2)}(SiW(12)O(40))] (3), where 5-Rsaltmen(2-) = N,N'-(1,1,2,2-tetramethylethylene)bis(5-R-salicylideneiminate) with R = MeO (methoxy), Br (bromo) and salen(2-) = N,N'-ethylenebis(salicylideneiminate). Compound 1 with a dianionic POM, [SW(12)O(40)](2-), is composed of a 1:1 aggregating set of [Mn(2)](2+)/POM, and 2, with a tetraanionic POM, [SiW(12)O(40)](4-), is a 2:1 set. Compound 3 with [SiW(12)O(40)](4-) forms a unique 1D coordinating chain with a [-{Mn(2)}-POM-](2-) repeating unit, for which a hydrogen-bonded dimeric unit ([Mn(5-Brsaltmen)(H(2)O)(acetone)](2)(2+)) is present as a countercation. Independent of the formula ratio of [Mn(2)](2+)/POM, Mn(III) dimers and POM units in 1-3 form respective segregated columns along a direction of the unit cell, which make an alternate packing to separate evenly identical species in a crystal. The nearest intermolecular Mn···Mn distance is found in the order 2 < 3 < 1. The segregation of the [Mn(2)](2+) dimer resulted in interdimer distances long enough to effectively reduce the intermolecular magnetic interaction, in particular in 1 and 3. Consequently, an intrinsic property, SMM behavior, of Mn(III) dimers has been characterized in this system, even though the interdimer interactions are still crucial in the case of 2, where a long-range magnetic order competitively affects slow relaxation of the magnetization at low ac frequencies.

Identification of 4-quinolone derivatives as inhibitors of reactive oxygen species production from human umbilical vein endothelial cells.

Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (25b), inhibited ROS production from HUVECs with an IC(50) of 140 nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.

Perspectives of Multidisciplinary Professional Teams during Assessment Processes for ATD Selection in the Japanese Public Provision System.

Selection of assistive technology devices (ATDs), which are imperative for persons with disabilities to improve their quality of life, requires collaboration of users and multidisciplinary professionals. However, it is still unknown how to design and implement an adequate collaborative work flow and a professional team. Under Japanese governmental ATD provision system, based on the application by clients, ATDs are mainly selected through collaborative processes with the clients and health professionals in public organizations, rehabilitation counseling centers (RCCs). By employing qualitative study methods in this study, we investigated the ATD selection process in which health professionals in RCCs collaboratively assess clients with physical disabilities so as to support them in selecting the adequate ATDs. To identify the perspectives required for ATD selection completely, the assessment processes were recorded and analyzed with a pseudo setting in two RCCs. Content analysis of the conversations between the client and professionals revealed the characteristics of the information exchanged in the assessment processes. A total of 760 assessment items were identified, thus indicating a broad array of interest. Despite the richness of information collected for the assessment, half of the assessment items did not have corresponding items in the documents that were employed during the prescription process. Thematic analysis of the interviews that followed revealed the common values and collaborative processes in ATD selection, which were shared and elaborated among the staff in daily social interactions. To facilitate implementation of ATD provision in various areas with few resources, it may be effective to convert this tacit-to-tacit knowledge sharing into a more explicit sharing by promoting analyses of good practices.

Assessment of driving skills of a mobility scooter using driving operation logs.

A mobility scooter is a major assistive technology that replaces human ambulatory functions for people with disabilities. A license is often not required for driving a mobility scooter; therefore, less skilled drivers might create safety concerns. An effective way of reducing these safety risks is by assessing the driving skills of users. The existing assessment measures mostly score the task performance using manual observations. In this study, we have developed a novel assessment system that logs the driving operations by using add-on sensors. This system can monitor the operations of a mobility scooter including the angles of the throttle lever and the steering tiller. The subjects were seven older adults who participated in the driving test involving six tasks; the driver performances were video recorded, and the vehicle operation data were logged. The video analysis showed that two subjects crashed their scooters into objects or made contact with objects during the test course. To extract the characteristic patterns of the operations from the logs, 2D histograms of the operational status durations were investigated for each subject and task. Subsequent analysis of the operation logs identified the two subjects who had crashed their vehicles during the test drive. Our results proved that the driving operation logs could be used complementarily as a simple and low-cost tool for assessing a person's driving skills.

Study of Relationship Between Mode of Conception and Non-Specific Psychological Distress in Women Undergoing Noninvasive Prenatal Testing.

BACKGROUND: Noninvasive prenatal testing (NIPT) has been performed worldwide to detect common fetal chromosomal aneuploidies. METHODS: Pregnant women (n=3743) with advanced maternal age who visited Nagoya University for NIPT were enrolled in this study. The K6 mental stress scores, that is non-specific psychological distress scores were obtained by questionnaires which were administered pre-NIPT and postpartum. High K6 scores (≥10) indicate anxiety or depression. The K6 stress scores at pre-NIPT and postpartum were evaluated about the relationship between mode of conception and non-specific psychological distress using binomial logistic regression. RESULTS: In general, 7.5% of pre-NIPT women (179/2393) and 5.1% of postpartum women (121/n) were found with high K6 scores. They also did not differ significantly based on maternal age, previous live birth, previous miscarriage, and mode of conception, i.e., natural conception, artificial insemination with husband (AIH), or assisted reproductive technology (ART). Moreover, the prenatal K6 scores were not significantly higher than those at postpartum. CONCLUSION: Our present data suggest that mental distress in women undergoing NIPT during pregnancy and after birth has no statistical relationship with maternal age, previous live birth, previous miscarriage, or infertility treatment, and continuous mental care may help reduce mental distress in the postpartum period.

Effects of synchronised engine sound and vibration presentation on visually induced motion sickness.

Driving simulator usage is often accompanied by motion sickness, and techniques for its prevention are not yet established. To reduce visually induced motion sickness (VIMS), we investigated the effects of synchronised presentation of engine sounds and motorcycle vibration on VIMS. A total of 80 participants experienced a driving scene with a head-mounted display for 5 minutes with or without synchronised presentation of engine sound and vibration. The results showed that VIMS scores, as measured by the Fast Motion Sickness scale, were significantly lower in participants who experienced the driving scene with sounds and vibration than in those who experienced the scene with sounds only, vibration only, or neither. Multiple regression analyses revealed that susceptibility to VIMS consistently explained the severity of VIMS to some extent but not with perceived realism of the virtual reality (VR) scene, sex, and experiences about VR devices and vehicles. This study demonstrated that simultaneous presentation of engine sounds and vibration, which were synchronous to each other and tightly coupled with the visual flow speed, effectively reduces VIMS while experiencing motorcycling simulators. The findings not only improve practical knowledge for reducing VIMS in driving simulators but also provide evidence for understanding the mechanisms of VIMS.

Importance of mediastinal screening-based observation during endoscopic ultrasound to examine gastrointestinal pathologies.

In all endoscopic ultrasound (EUS) examinations performed at our hospital, the heart, vasculature, and mediastinal lymph nodes from the esophagus are observed after checking for gastrointestinal pathologies. Since the introduction of EUS using a convex linear-array echoendoscope at our hospital in April 2015, EUS examinations have been performed in 371 cases for examining pancreaticobiliary diseases, submucosal tumors, and other pathologies during the 3-year period, till March 2018. We diagnosed 2 patients with asymptomatic cardiovascular disease while observing the mediastinum during EUS examination to examine identified pancreaticobiliary disease. No subjective symptoms associated with cardiovascular disease were observed and the respective conditions had not been identified previously in either case. One case involved a left atrial myxoma while the other involved a saccular aortic aneurysm in the thoracic aorta. A left atrial tumor resection and aortic replacement surgery were performed in each case. Their postoperative courses have been favorable. As cardiovascular diseases are often life-threatening, as in the present 2 cases, observational screening of the cardiovascular system from the esophagus should also be performed during EUS examinations just as the pharyngeal region is examined during upper gastrointestinal endoscopy.

Clinical utility of decorin in follicular fluid as a biomarker of oocyte potential.

This study investigated the concentration of decorin (DCN) in mature follicular fluid and the existence in the granulosa cells. It also investigated whether DCN is useful as a biomarker for outcomes of assisted reproductive technology (ART). A retrospective cohort study was performed involving 130 oocytes of 88 patients treated with ART because of unexplained infertility. The concentration of DCN in the follicular fluid (F-DCN) was 39.26ng/ml (median value); it was higher than that in serum. F-DCN of the oocytes fertilized by intracytoplasmic sperm injection (ICSI) was significantly lower than that of oocytes that were not fertilized (33.24ng/ml vs 40.18ng/ml; P=0.043). When a cut-off level of 34.5ng/ml was set according to the receiver-operating characteristic curve, the fertilization rate of the oocytes from the follicles in which F-DCN was lower than the cut-off level tended to be good compared to that of the oocytes with F-DCN higher than the cut-off level (P=0.052). DCN is less likely to be produced by the granulosa cells (GCs), because it was not detected in GCs by immunostaining and Western blot analysis. F-DCN has a possibility to be a biomarker indicating the quality of oocytes collected from the corresponding follicle.

Evaluation of the effects of mastication and swallowing on gastric motility using electrogastrography.

OBJECTIVES: The influence of mastication and swallowing on gastric motor function was evaluated by electrogastrography (EGG) and abdominal ultrasonography. METHODS: The subjects were 30 elderly patients with tubal feeding without mastication and swallowing (T group) and 30 elderly controls who processed food by mastication and swallowing (C group). Gastric motor function was percutaneously examined before and after the ingestion of 250 ml of a liquid diet using an electrogastrograph (NIPRO EGG, A and D, Tokyo, Japan). The cross-sectional area of the gastric antrum was measured at 1 and 30 min after the start of ingestion of the liquid diet by external ultrasonography of the abdomen, and the gastric excretion function was evaluated. Furthermore, the spectral analysis of heart rate variability was performed using Holter electrocardiograms before and after ingestion. The low frequency power (LF power, 0.04-0.15 Hz), high frequency power (HF power, 0.15-0.40 Hz), and the LF/HF ratio were determined. RESULTS: The peak amplitude at 3 cycles per minute (cpm) was significantly increased after ingestion in the C and T groups (p<0.05), and the ratio of increase was significantly lower in the T group (p<0.05). The mean amplitude for the brady-gastria and tachy-gastria was significantly higher in the T group than in the C group (p<0.05). The gastric excretion function, as evaluated by external ultrasonography of the abdomen, was significantly lower in the T group than in the C group (p<0.05). An analysis of heart rate variability demonstrated that the HF power, a parameter of parasympathetic activity, after ingestion was significantly higher in the C group than in the T group (p<0.05). No changes in LF power or LF/HF ratio, parameters of sympathetic activity, were induced by ingestion in either the C or T groups. CONCLUSIONS: The parasympathetic nerve dominantly controls gastric motor function, but autonomic nervous activity is reduced in patients who are unable to masticate and swallow food, resulting in adverse effects on gastric motor function and excretion function. Mastication and swallowing not only prepare food for passage from the oral cavity to the esophagus but are also important in terms of subsequent events that occur in stomach. It has been proposed that autonomic nervous activity might be involved in mastication and swallowing.

A new class of nonpeptide bradykinin B(2) receptor ligand, incorporating a 4-aminoquinoline framework. Identification of a key pharmacophore to determine species difference and agonist/antagonist profile.

Introduction of various aliphatic amino groups at the 4-position of the quinoline moiety of our nonpeptide bradykinin (BK) B(2) receptor antagonists afforded highly potent ligands for human B(2) receptor with various affinities for guinea pig B(2) receptor, indicating remarkable species difference. A representative 4-dimethyamino derivative 40a exhibited subnanomolar and nanomolar binding affinities for human and guinea pig B(2) receptors, respectively, and significantly inhibited BK-induced bronchoconstriction in guinea pigs at 10 microg/kg by intravenous administration. Further chemical modification led us to discover unique partial agonists for the human B(2) receptor that increase inositol phosphates (IPs) production by themselves in Chinese hamster ovary (CHO) cells expressing the cloned human B(2) receptor. Although their potency and efficacy were much lower than those of BK, we identified them as screening leads for nonpeptide B(2) agonists. In these studies it was revealed the 4-substituent of the quinoline moiety is the key pharmacophore to determine species difference and agonist/antagonist profiles.

Discovery of the first non-peptide full agonists for the human bradykinin B(2) receptor incorporating 4-(2-picolyloxy)quinoline and 1-(2-picolyl)benzimidazole frameworks.

In the course of our studies on non-peptide bradykinin (BK) B(2) receptor ligands, it was suggested that the 4-substituent of the quinoline ring may play a critical role in determining binding affinities for human and guinea pig B(2) receptors, as well as agonist/antagonist properties. We carried out an extensive investigation to elucidate the structure-activity relationships (SAR) for this key pharmacophore. Introduction of lower alkoxy groups to the 4-position of the quinoline ring of 3 led to the identification of 4-ethoxy derivative 22b as a unique partial agonist. This compound significantly stimulated inositol phosphates (IPs) formation in Chinese hamster ovary cells expressing the cloned human B(2) receptor at concentrations greater than 10 nM and displayed one-tenth of the intrinsic activity of BK. The agonist activity of 22b was selective for the B(2) receptor and was inhibited by selective peptide and non-peptide B(2) antagonists. On the other hand, 22b strongly suppressed BK-induced IPs formation through the cloned human B(2) receptor. Further studies on the key pharmacophore led to identification of a 2-picolyloxy moiety as a powerful agonist switch, leading to the discovery of a potent and efficacious non-peptide B(2) agonist, 19a. Successive optimization of the acyl side chain afforded 38, which exhibited full agonist activity on stimulation of IPs formation. Furthermore, this strategy could be applied successfully to the benzimidazole series. The representative 1-(2-picolyl)benzimidazole derivative 47c increased PGE(2) production at a 1 microM concentration to the same level as the maximum effect of BK. Thus, we have established the medicinal chemistry modifications required to convert our highly potent non-peptide B(2) antagonists to agonists with potent efficacy.

A new series of highly potent non-peptide bradykinin B2 receptor antagonists incorporating the 4-heteroarylquinoline framework. Improvement of aqueous solubility and new insights into species difference.

Introduction of nitrogen-containing heteroaromatic groups at the 4-position of the quinoline moiety of our non-peptide B(2) receptor antagonists resulted in enhancing binding affinities for the human B(2) receptor and reducing binding affinities for the guinea pig one, providing new structural insights into species difference. A CoMFA study focused on the diversity of the quinoline moiety afforded correlative and predictive QSAR models of binding for the human B(2) receptor but not for the guinea pig one. A series of 4-(1-imidazolyl)quinoline derivatives could be dissolved in a 5% aqueous solution of citric acid up to a concentration of 10 mg/mL. A representative compound 48a inhibited the specific binding of [(3)H]BK to the cloned human B(2) receptor expressed in Chinese hamster ovary cells with an IC(50) value of 0.26 nM and significantly inhibited BK-induced bronchoconstriction in guinea pigs even at 1 microg/kg by intravenous administration.