Psychosocial Impacts of Infertility among Omani Women with Polycystic Ovarian Syndrome: A Qualitative Study.

BACKGROUND: To understand the psychosocial experience of infertility among women with polycystic ovarian syndrome in Oman. MATERIALS AND METHODS: In this qualitative study, semi-structured interviews were conducted with 20 Omani women diagnosed with polycystic ovarian syndrome (PCOS) and infertility across two fertility clinics, in Muscat-Oman. Interviews were audio-recorded, transcribed analysed verbatim and qualitatively using the framework approach. RESULTS: Four main themes emerged from participants' interviews related to the cultural aspects around infertility, the impact of infertility on participants' emotions, the effects of infertility on couples' relationship and self-management strategies for dealing with infertility. Culturally, women are expected to conceive soon after marriage, and most participants were blamed for the delay rather than their husbands. Participants experienced psychosocial pressure to bear children, mainly from in laws, where some admitted that their husbands' family suggested they remarried for having children. The majority of women mentioned being emotionally supported by their partners; however marital tensions in the form of negative emotions and threats of divorce were apparent in couples that had been experiencing infertility for longer time. Women were emotionally feeling lonely, jealous and inferior to other women with children and concerned that they would not have children to look after them in older age. Although women who had experienced infertility for a greater duration seemed to become more resilient and cope better, other participants described how they were using different strategies to cope with infertility including taking up new activities; whereas others admitted moving out from their in laws' house or avoiding social gatherings where the topic of children was likely to come up. CONCLUSION: Omani women with PCOS and infertility experience significant psychosocial challenges given the high value placed on fertility within the culture as a result they seem to adapt a variety of coping strategies. Health care providers may consider offering emotional support during consultations.

Analysis of sociodemographic and clinical factors associated with Lassa fever disease and mortality in Nigeria.

Over past decades, there has been increasing geographical spread of Lassa fever (LF) cases across Nigeria and other countries in West Africa. This increase has been associated with significant morbidity and mortality despite increasing focus on the disease by both local and international scientists. Many of these studies on LF have been limited to few specialised centres in the country. This study was done to identify sociodemographic and clinical predictors of LF disease and related deaths across Nigeria. We analysed retrospective surveillance data on suspected LF cases collected during January-June 2018 and 2019. Multivariable logistic regression analyses were used to identify the factors independently associated with laboratory-confirmed LF diagnosis, and with LF-related deaths. There were confirmed 815 of 1991 suspected LF cases with complete records during this period. Of these, 724/815 confirmed cases had known clinical outcomes, of whom 100 died. LF confirmation was associated with presentation of gastrointestinal tract (aOR 3.47, 95% CI: 2.79-4.32), ear, nose and throat (aOR 2.73, 95% CI: 1.80-4.15), general systemic (aOR 2.12, 95% CI: 1.65-2.70) and chest/respiratory (aOR 1.71, 95% CI: 1.28-2.29) symptoms. Other factors were being male (aOR 1.32, 95% CI: 1.06-1.63), doing business/trading (aOR 2.16, 95% CI: 1.47-3.16) and farming (aOR 1.73, 95% CI: 1.12-2.68). Factors associated with LF mortality were a one-year increase in age (aOR 1.03, 95% CI: 1.01-1.04), bleeding (aOR 2.07, 95% CI: 1.07-4.00), and central nervous manifestations (aOR 5.02, 95% CI: 3.12-10.16). Diverse factors were associated with both LF disease and related death. A closer look at patterns of clinical variables would be helpful to support early detection and management of cases. The findings would also be useful for planning preparedness and response interventions against LF in the country and region.

Assessing the capacity of symptom scores to predict COVID-19 positivity in Nigeria: a national derivation and validation cohort study.

OBJECTIVES: This study aimed to develop and validate a symptom prediction tool for COVID-19 test positivity in Nigeria. DESIGN: Predictive modelling study. SETTING: All Nigeria States and the Federal Capital Territory. PARTICIPANTS: A cohort of 43 221 individuals within the national COVID-19 surveillance dataset from 27 February to 27 August 2020. Complete dataset was randomly split into two equal halves: derivation and validation datasets. Using the derivation dataset (n=21 477), backward multivariable logistic regression approach was used to identify symptoms positively associated with COVID-19 positivity (by real-time PCR) in children (≤17 years), adults (18-64 years) and elderly (≥65 years) patients separately. OUTCOME MEASURES: Weighted statistical and clinical scores based on beta regression coefficients and clinicians' judgements, respectively. Using the validation dataset (n=21 744), area under the receiver operating characteristic curve (AUROC) values were used to assess the predictive capacity of individual symptoms, unweighted score and the two weighted scores. RESULTS: Overall, 27.6% of children (4415/15 988), 34.6% of adults (9154/26 441) and 40.0% of elderly (317/792) that had been tested were positive for COVID-19. Best individual symptom predictor of COVID-19 positivity was loss of smell in children (AUROC 0.56, 95% CI 0.55 to 0.56), either fever or cough in adults (AUROC 0.57, 95% CI 0.56 to 0.58) and difficulty in breathing in the elderly (AUROC 0.53, 95% CI 0.48 to 0.58) patients. In children, adults and the elderly patients, all scoring approaches showed similar predictive performance. CONCLUSIONS: The predictive capacity of various symptom scores for COVID-19 positivity was poor overall. However, the findings could serve as an advocacy tool for more investments in resources for capacity strengthening of molecular testing for COVID-19 in Nigeria.

Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic.

A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.

Opioids and the Risk of Fracture: A Self-Controlled Case Series Study in the Clinical Practice Research Datalink.

Self-controlled study designs can be used to assess the association between exposures and acute outcomes while controlling for important confounders. Using routinely collected health data, a self-controlled case series design was used to investigate the association between opioid use and bone fractures in 2008-2017 among adults registered in the United Kingdom Clinical Practice Research Datalink. The relative incidence of fracture was estimated, comparing periods when these adults were exposed and unexposed to opioids, adjusted for time-varying confounders. Of 539,369 people prescribed opioids, 67,622 sustained fractures and were included in this study. The risk of fracture was significantly increased when the patient was exposed to opioids, with an adjusted incidence rate ratio of 3.93 (95% confidence interval (CI): 3.82, 4.04). Fracture risk was greatest in the first week of starting opioid use (adjusted incidence rate ratio: 7.81, 95% CI: 7.40, 8.25) and declined with increasing duration of use. Restarting opioid use after a gap in exposure significantly increased fracture risk (adjusted incidence rate ratio: 5.05, 95% CI: 4.83, 5.29) when compared with nonuse. These findings highlight the importance of raising awareness of fractures among patients at opioid initiation and demonstrate the utility of self-controlled methods for pharmacoepidemiologic research.

Early childhood respiratory morbidity and antibiotic use in ex-preterm infants: a primary care population-based cohort study.

BACKGROUND: Globally, bronchopulmonary dysplasia (BPD) continues to increase in preterm infants. Recent studies exploring subsequent early childhood respiratory morbidity have been small or focused on hospital admissions. AIMS: To examine early childhood rates of primary care consultations for respiratory tract infections (RTI), lower respiratory tract infections (LRTI), wheeze and antibiotic prescriptions in ex-preterm and term children. A secondary aim was to examine differences between preterm infants discharged home with or without oxygen. METHODS: Retrospective cohort study using linked electronic primary care and hospital databases of children born between 1997 and 2014. We included 253 277 eligible children, with 1666 born preterm at <32 weeks' gestation, followed-up from primary care registration to age 5 years. Adjusted incidence rate ratios (aIRRs) were calculated. RESULTS: Ex-preterm infants had higher rates of morbidity across all respiratory outcomes. After adjusting for confounders, aIRRs for RTI (1.37, 95% CI 1.33-1.42), LRTI (2.79, 95% CI 2.59-3.01), wheeze (3.05, 95% CI 2.64-3.52) and antibiotic prescriptions (1.49, 95% CI 1.44-1.55) were higher for ex-preterm infants. Ex-preterm infants discharged home on oxygen had significantly greater morbidity across all respiratory diagnoses and antibiotic prescriptions compared to those without home oxygen. The highest rates of respiratory morbidity were observed in children from the most deprived socioeconomic groups. CONCLUSION: Ex-preterm infants, particularly those with BPD requiring home oxygen, have significant respiratory morbidity and antibiotic prescriptions in early childhood. With the increasing prevalence of BPD, further research should focus on strategies to reduce the burden of respiratory morbidity in these high-risk infants after hospital discharge.

Epidemiology of bronchiectasis in the UK: Findings from the British lung foundation's 'Respiratory health of the nation' project.

Key findings of this national survey of non-cystic fibrosis bronchiectasis epidemiology were that its prevalence, incidence and mortality have all increased over recent years; we estimate that around 212,000 people are currently living with bronchiectasis in the UK, very much higher than commonly quoted figures. Bronchiectasis is more common in females than males; 60% of diagnoses are made in the over-70 age group. Regional differences in prevalence, incidence, mortality, and hospital admission were identified. An intriguing finding was that bronchiectasis is more commonly diagnosed in the least deprived sections of the population, in contrast to other respiratory disorders.

Predicting fracture risk in patients with chronic obstructive pulmonary disease: a UK-based population-based cohort study.

OBJECTIVE: To assess the incidence of hip fracture and all major osteoporotic fractures (MOF) in patients with chronic obstructive pulmonary disease (COPD) compared with non-COPD patients and to evaluate the use and performance of fracture risk prediction tools in patients with COPD. To assess the prevalence and incidence of osteoporosis. DESIGN: Population-based cohort study. SETTING: UK General Practice health records from The Health Improvement Network database. PARTICIPANTS: Patients with an incident COPD diagnosis from 2004 to 2015 and non-COPD patients matched by age, sex and general practice were studied. OUTCOMES: Incidence of fracture (hip alone and all MOF); accuracy of fracture risk prediction tools in COPD; and prevalence and incidence of coded osteoporosis. METHODS: Cox proportional hazards models were used to assess the incidence rates of osteoporosis, hip fracture and MOF (hip, proximal humerus, forearm and clinical vertebral fractures). The discriminatory accuracies (area under the receiver operating characteristic [ROC] curve) of fracture risk prediction tools (FRAX and QFracture) in COPD were assessed. RESULTS: Patients with COPD (n=80 874) were at an increased risk of fracture (both hip alone and all MOF) compared with non-COPD patients (n=308 999), but this was largely mediated through oral corticosteroid use, body mass index and smoking. Retrospectively calculated ROC values for MOF in COPD were as follows: FRAX: 71.4% (95% CI 70.6% to 72.2%), QFracture: 61.4% (95% CI 60.5% to 62.3%) and for hip fracture alone, both 76.1% (95% CI 74.9% to 77.2%). Prevalence of coded osteoporosis was greater for patients (5.7%) compared with non-COPD patients (3.9%), p<0.001. The incidence of osteoporosis was increased in patients with COPD (n=73 084) compared with non-COPD patients (n=264 544) (adjusted hazard ratio, 1.13, 95% CI 1.05 to 1.22). CONCLUSION: Patients with COPD are at an increased risk of fractures and osteoporosis. Despite this, there is no systematic assessment of fracture risk in clinical practice. Fracture risk tools identify those at high risk of fracture in patients with COPD.

Assessment of discharge treatment prescribed to women admitted to hospital for hyperemesis gravidarum.

AIMS: Prescribing drug treatment for the management of hyperemesis gravidarum (HG), the most severe form of nausea and vomiting in pregnancy, remains controversial. Since most manufacturers do not recommend prescribing antiemetics during pregnancy, little is known regarding which treatments are most prevalent among pregnant patients. Here, we report for the first time, evidence of actual treatments prescribed in English hospitals. METHODS: A retrospective pregnancy cohort was constructed using anonymised electronic records in the Nottingham University Hospitals Trust system for all women who delivered between January 2010 and February 2015. For women admitted to hospital for HG, medications prescribed on discharge were described and variation by maternal characteristics was assessed. Compliance with local and national HG treatment guidelines was evaluated. RESULTS: Of 33 567 pregnancies (among 30 439 women), the prevalence of HG was 1.7%. Among 530 HG admissions with records of discharge drugs, cyclizine was the most frequently prescribed (almost 73% of admissions). Prochlorperazine and metoclopramide were prescribed mainly in combination with other drugs; however, ondansetron was more common than metoclopramide at discharge from first and subsequent admissions. Steroids were only prescribed following readmissions. Thiamine was most frequently prescribed following readmission while high dose of folic acid was prescribed equally after first or subsequent admissions. Prescribing showed little variation by maternal age, ethnicity, weight, socioeconomic deprivation, or comorbidities. CONCLUSION: Evidence that management of HG in terms of discharge medications mainly followed local and national recommendations provides reassurance within the health professional community. Wider documentation of drugs prescribed to women with HG is required to enable full assessment of whether optimal drug management is being achieved.

Linkage of national soil quality measurements to primary care medical records in England and Wales: a new resource for investigating environmental impacts on human health.

BACKGROUND: Long-term, low-level exposure to toxic elements in soil may be harmful to human health but large longitudinal cohort studies with sufficient follow-up time to study these effects are cost-prohibitive and impractical. Linkage of routinely collected medical outcome data to systematic surveys of soil quality may offer a viable alternative. METHODS: We used the Geochemical Baseline Survey of the Environment (G-BASE), a systematic X-ray fluorescence survey of soil inorganic chemistry throughout England and Wales to obtain estimates of the concentrations of 15 elements in the soil contained within each English and Welsh postcode area. We linked these data to the residential postcodes of individuals enrolled in The Health Improvement Network (THIN), a large database of UK primary care medical records, to provide estimates of exposure. Observed exposure levels among the THIN population were compared with expectations based on UK population estimates to assess representativeness. RESULTS: Three hundred seventy-seven of three hundred ninety-five English and Welsh THIN practices agreed to participate in the linkage, providing complete residential soil metal estimates for 6,243,363 individuals (92% of all current and former patients) with a mean period of prospective computerised medical data collection (follow-up) of 6.75 years. Overall agreement between the THIN population and expectations was excellent; however, the number of participating practices in the Yorkshire & Humber strategic health authority was low, leading to restricted ranges of measurements for some elements relative to the known variations in geochemical concentrations in this area. CONCLUSIONS: The linked database provides unprecedented population size and statistical power to study the effects of elements in soil on human health. With appropriate adjustment, results should be generalizable to and representative of the wider English and Welsh population.

Mitochondrial ROS cause motor deficits induced by synaptic inactivity: Implications for synapse pruning.

Developmental synapse pruning refines burgeoning connectomes. The basic mechanisms of mitochondrial reactive oxygen species (ROS) production suggest they select inactive synapses for pruning: whether they do so is unknown. To begin to unravel whether mitochondrial ROS regulate pruning, we made the local consequences of neuromuscular junction (NMJ) pruning detectable as motor deficits by using disparate exogenous and endogenous models to induce synaptic inactivity en masse in developing Xenopus laevis tadpoles. We resolved whether: (1) synaptic inactivity increases mitochondrial ROS; and (2) chemically heterogeneous antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bungarotoxin), nerve (α-latrotoxin) targeted neurotoxins or an endogenous pruning cue (SPARC), synaptic inactivity increased mitochondrial ROS in vivo. The manganese porphyrins MnTE-2-PyP5+ and/or MnTnBuOE-2-PyP5+ blocked mitochondrial ROS to significantly reduce neurotoxin and endogenous pruning cue induced motor deficits. Selectively inducing mitochondrial ROS-using mitochondria-targeted Paraquat (MitoPQ)-recapitulated synaptic inactivity induced motor deficits; which were significantly reduced by blocking mitochondrial ROS with MnTnBuOE-2-PyP5+. We unveil mitochondrial ROS as synaptic activity sentinels that regulate the phenotypical consequences of forced synaptic inactivity at the NMJ. Our novel results are relevant to pruning because synaptic inactivity is one of its defining features.

Risk of fall in patients with COPD.

A matched cohort study was conducted to determine the incidence of falls in patients following a diagnosis of COPD using a UK primary care database. 44 400 patients with COPD and 175 545 non-COPD subjects were identified. The incidence rate of fall per 1000 person-years in patients with COPD was higher (44.9; 95% CI 44.1 to 45.8) compared with non-COPD subjects (24.1; 95% CI 23.8 to 24.5) (P<0.0001). Patients with COPD were 55% more likely to have an incident record of fall than non-COPD subjects (adjusted HR, 1.55; 95% CI 1.50 to 1.59). The greater falls risk in patients with COPD needs consideration and modifiable factors addressed.

Adverse Maternal and Birth Outcomes in Women Admitted to Hospital for Hyperemesis Gravidarum: a Population-Based Cohort Study.

BACKGROUND: Evidence for risks of adverse maternal and birth outcomes in women with hyperemesis gravidarum (HG) is predominantly from small studies, unknown, or conflicting. METHODS: A population-based cohort study using secondary health care records (Hospital Episode Statistics covering all of England from 1997 to 2012) was used to calculate odds ratios (OR) with 99% confidence intervals (CI) for the association between HG hospital admission and adverse outcomes, adjusting for maternal and pregnancy confounders. RESULTS: Within 8 211 850 pregnancies ending in live births or stillbirths, women with HG had increased odds of anaemia (OR 1.28, 99% CI 1.23, 1.33), preeclampsia (OR 1.16, 99% CI 1.09, 1.22), eclampsia (OR 1.84, 99% CI 1.07, 3.18), venous thromboembolism antenatally (OR 1.94, 99% CI 1.57, 2.39 for deep vein thrombosis, and OR 2.54, 99% CI 1.89, 3.40 for pulmonary embolism) and post-partum. Odds of stillbirth (OR 0.77, 99% CI 0.66, 0.89) and post-term (OR 0.86, 99% CI 0.81, 0.92) delivery were decreased. Women were more likely to be induced (OR 1.20, 99% CI 1.16, 1.23), to deliver preterm (OR 1.11, 99% CI 1.05, 1.17), very preterm (OR 1.18, 99% CI 1.05, 1.32), or by caesarean section (OR 1.12, 99% CI 1.08, 1.16), to have low birthweight (OR 1.12, 99% CI 1.08, 1.17) or small for gestational age (OR 1.06, 99% CI 1.01, 1.11) babies and although absolute risks were small, their offspring were more likely to undergo resuscitation or neonatal intensive care. CONCLUSION: HG may have important antenatal and postnatal consequences that should be considered in communications between health care professionals and women to best manage HG and prevent progression during pregnancy.

Timing of onset of symptoms in people with idiopathic pulmonary fibrosis.

Little is known about when symptoms of idiopathic pulmonary fibrosis first develop. We identified incident cases of idiopathic pulmonary fibrosis-clinical syndrome (IPF-CS) from a UK primary care database and assessed the frequency of consultations for common symptoms in the 5 years prior to diagnosis. 1671 cases were identified with 5 years of data prior to diagnosis. Breathlessness was the most common symptom, followed by cough. Cases were significantly more likely than controls to experience these symptoms (p<0.001), even 4-5 years before diagnosis (OR for breathlessness for this period 2.79, 95% CI 2.13 to 3.65). This suggests that some patients with IPF may be symptomatic for more than 5 years before diagnosis.

The recording and characteristics of pulmonary rehabilitation in patients with COPD using The Health Information Network (THIN) primary care database.

Pulmonary rehabilitation is recommended for patients with COPD to improve physical function, breathlessness and quality of life. Using The Health Information Network (THIN) primary care database in UK, we compared the demographic and clinical parameters of patients with COPD in relation to coding of pulmonary rehabilitation, and to investigate whether there is a survival benefit from pulmonary rehabilitation. We identified patients with COPD, diagnosed from 2004 and extracted information on demographics, pulmonary rehabilitation and clinical parameters using the relevant Read codes. Thirty six thousand one hundred and eighty nine patients diagnosed with COPD were included with a mean (SD) age of 67 (11) years, 53% were male and only 9.8% had a code related to either being assessed, referred, or completing pulmonary rehabilitation ever. Younger age at diagnosis, better socioeconomic status, worse dyspnoea score, current smoking, and higher comorbidities level are more likely to have a record of pulmonary rehabilitation. Of those with a recorded MRC of 3 or worse, only 2057 (21%) had a code of pulmonary rehabilitation. Survival analysis revealed that patients with coding for pulmonary rehabilitation were 22% (95% CI 0.69-0.88) less likely to die than those who had no coding. In UK THIN records, a substantial proportion of eligible patients with COPD have not had a coded pulmonary rehabilitation record. Survival was improved in those with PR record but coding for other COPD treatments were also better in this group. GP practices need to improve the coding for PR to highlight any unmet need locally. CHRONIC LUNG DISEASE: ROLLING OUT THE REHAB: Analysis of recent UK data suggests that more patients with chronic lung disease could benefit from lung rehabilitation programmes. During pulmonary rehabilitation (PR), patients with chronic obstructive pulmonary disease (COPD) work with specialists to learn exercises and optimise breathing techniques. The programmes are recommended under current guidelines, particularly for patients with a high breathlessness score. Despite this, when Charlotte Bolton and co-workers at the University of Nottingham analysed 36,189 patient primary care records gathered since 2004, they found only 9.8% of COPD patients had ever had a coded record of being assessed, referred for, or undertaken PR. Those patients who completed PR were 22% less likely to die that those who didn't, although appeared they had also received better overall COPD care. Current smokers, those suffering from co-morbidities and younger patients were more likely to receive PR than other patient groups.

Discovery of Spirocyclic Aldosterone Synthase Inhibitors as Potential Treatments for Resistant Hypertension.

Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.

Discovery of novel non-steroidal reverse indole mineralocorticoid receptor antagonists.

Reported herein are a series of reverse indoles that represent novel non-steroidal mineralocorticoid receptor (MR) antagonists. The key structure-activity relationships (SAR) are presented below. This reverse indole series is exemplified by a compound that demonstrated efficacy in an acute natriuresis rodent model comparable to marketed MR antagonists, spironolactone and eplerenone.

Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

A supervised adverse drug reaction signalling framework imitating Bradford Hill's causality considerations.

Big longitudinal observational medical data potentially hold a wealth of information and have been recognised as potential sources for gaining new drug safety knowledge. Unfortunately there are many complexities and underlying issues when analysing longitudinal observational data. Due to these complexities, existing methods for large-scale detection of negative side effects using observational data all tend to have issues distinguishing between association and causality. New methods that can better discriminate causal and non-causal relationships need to be developed to fully utilise the data. In this paper we propose using a set of causality considerations developed by the epidemiologist Bradford Hill as a basis for engineering features that enable the application of supervised learning for the problem of detecting negative side effects. The Bradford Hill considerations look at various perspectives of a drug and outcome relationship to determine whether it shows causal traits. We taught a classifier to find patterns within these perspectives and it learned to discriminate between association and causality. The novelty of this research is the combination of supervised learning and Bradford Hill's causality considerations to automate the Bradford Hill's causality assessment. We evaluated the framework on a drug safety gold standard known as the observational medical outcomes partnership's non-specified association reference set. The methodology obtained excellent discrimination ability with area under the curves ranging between 0.792 and 0.940 (existing method optimal: 0.73) and a mean average precision of 0.640 (existing method optimal: 0.141). The proposed features can be calculated efficiently and be readily updated, making the framework suitable for big observational data.

Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.