Identification of novel azaindazole CCR1 antagonist clinical candidates.

Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.

Discovery and optimization of pyrazole amides as antagonists of CCR1.

A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.

Complete resolution of postoperative hemiparesis following carotid endarterectomy with therapeutic hypothermia: a case study and literature review.

Therapeutic hypothermia is indicated in a number of traumatic brain injuries as well as for cardiovascular shock (Warner DS, James ML, Laskowitz, et al. Translational research in acute central nervous system injury: lessons learned and the future. JAMA Neurol 2014;71:1311-1318), but it has been limited in its application to acute ischemic stroke. We present the case of a 65-year-old woman with a clinical cerebrovascular accident following a right carotid endarterectomy who was treated with a 24-hr hypothermia protocol and had a full recovery. The hypothermia protocol utilized on this patient and a review of the literature surrounding hypothermia in the setting of ischemic stroke are presented.

Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore.

Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.

Diagnostic Value of Cone-Beam Computed Tomography and Digital Periapical Radiography in Detection of Separated Instruments.

Introduction: File Fracture is one of the most common problems during root canal treatment which can affect treatment procedure and prognosis, so it is important to diagnose and prevent it. The aim of this study was to evaluate and compare the diagnostic value of cone-beam computed tomography (CBCT) and digital periapical radiography for detection of separated instrument retained inside the canal. Methods and Materials: Ninety single-rooted extracted human teeth were selected and randomly divided into 3 groups (n=30). Group 1, separated file #10 at the 2-mm apical third of the root canal; group 2, separated file #35 at the 2-mm apical third of the root canal; and group 3, without a broken file (control group). The teeth were instrumented to size #30 and were shaped to size #55 and then the canals were obturated up to separated instrument, or the working length for the teeth without a separated instrument, with lateral condensation technique. After that all teeth were placed in dry skull, digital radiography and CBCT was taken. After data collection, data was analyzed using SPSS software by means of sensitivity, specificity, positive and negative predictive values, and frequency tables. Results: Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of digital periapical radiography in detection of a fractured file #10 in the canal was 96.7% and 63.3%, 76.7%, 73.1%, 67.6%, 70%, for CBCT, respectively. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of digital periapical radiography in detection of a fracture file #35 in the canal was 93.3%, 96.7%, 96.6%, 93.5% and 95%, and 36.7%, 76.7%, 61.1%, 54.8%, 56.66%, for CBCT, respectively. Conclusion: Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of digital periapical radiography was better than the CBCT technique in both sizes of broken files.

Diagnosis of Obstructive Sleep Apnea Syndrome in Adults: A Brief Review of Existing Data for Practice in Iran.

Obstructive sleep apnea (OSA) is a common disorder associated with major comorbidities. It is estimated that 5-35% of the adult population in Iran are at high risk for OSA. This review article is designed to assist sleep medicine specialists as well as general practitioners in Iran to screen for OSA. It summarizes empirical data for diagnosing OSA including history taking, physical examination, diagnostic testing, and diagnostic criteria with regards to existing sleep medicine centers and availability of diagnostic tests in Iran.

A hypothesis on the most prevalent psychological type for chief residents in the field of internal medicine.

Communication is the key to good doctor-patient relations. Resident learning occurs through the process of observation and role modeling. We hypothesize that the most prevalent personality type for chief residents will be in discordance with the most prevalent type (Sensor) in the general population. We set out to determine the communication styles of a national sampling of recent chief residents in the field of medicine. The survey based on Jung's Psychological types: thinker, feeler, the intuitor and sensor. Overall self report of psychological types revealed the majority, both male and female (45.6%) to be in the 'feeler' category. Feelers are described as persons with a high need for interpersonal harmony. They value compassion and empathy and enjoy meeting other people's needs.

Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate.

A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.

CCR1 plays a critical role in modulating pain through hematopoietic and non-hematopoietic cells.

Inflammation is associated with immune cells infiltrating into the inflammatory site and pain. CC chemokine receptor 1 (CCR1) mediates trafficking of leukocytes to sites of inflammation. However, the contribution of CCR1 to pain is incompletely understood. Here we report an unexpected discovery that CCR1-mediated trafficking of neutrophils and CCR1 activity on non-hematopoietic cells both modulate pain. Using a genetic approach (CCR1-/- animals) and pharmacological inhibition of CCR1 with selective inhibitors, we show significant reductions in pain responses using the acetic acid-induced writhing and complete Freund's adjuvant-induced mechanical hyperalgesia models. Reductions in writhing correlated with reduced trafficking of myeloid cells into the peritoneal cavity. We show that CCR1 is highly expressed on circulating neutrophils and their depletion decreases acetic acid-induced writhing. However, administration of neutrophils into the peritoneal cavity did not enhance acetic acid-induced writhing in wild-type (WT) or CCR1-/- mice. Additionally, selective knockout of CCR1 in either the hematopoietic or non-hematopoietic compartments also reduced writhing. Together these data suggest that CCR1 functions to significantly modulate pain by controlling neutrophil trafficking to the inflammatory site and having an unexpected role on non-hematopoietic cells. As inflammatory diseases are often accompanied with infiltrating immune cells at the inflammatory site and pain, CCR1 antagonism may provide a dual benefit by restricting leukocyte trafficking and reducing pain.

Nonsteroidal dissociated glucocorticoid agonists containing azaindoles as steroid A-ring mimetics.

Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.

Recent progress in the discovery of novel glucocorticoid receptor modulators.

Glucocorticoids have been used in modern clinical practice for over fifty years. Although they have demonstrated potent anti-inflammatory and immunosuppressive activities, their association with debilitating and life-threatening side effects has been a major drawback. Recent insights into glucocorticoid biology have lent support to the hypothesis that the glucocorticoid anti-inflammatory activities could be dissociated from their adverse side effects. Inspired by these biological findings, the search for dissociated glucocorticoid receptor agonists has intensified. Antag-onists of the glucocorticoid receptor that offer therapeutic benefits for the treatment of diseases such as diabetes have also been pursued. These efforts have been partly focused on the development of tissue, especially liver, selective glucocor-ticoid receptor antagonists, which are thought to have improved safety profiles. This review offers a summary of the research and development activities in this field and covers journal and patent publications from 2003 to March 2006.

Design, synthesis, and evaluation of oxazole transthyretin amyloidogenesis inhibitors.

Ten oxazoles bearing a C(4) carboxyl group were synthesized and evaluated as transthyretin (TTR) amyloid fibril inhibitors. Substituting aryls at the C(2) position of the oxazole ring reveals that a 3,5-dichlorophenyl substituent significantly reduced amyloidogenesis. The efficacy of these inhibitors was enhanced further by installing an ethyl, a propyl, or a CF(3) group at the C(5) position. The CF(3) substitution at C(5) also improves the TTR binding selectivity over all the other proteins in human blood.