Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists

Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.     

Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Na(v)1.7 antagonists

Herein we describe the discovery, optimization, and structure-activity relationships of novel potent pyrrolopyrimidine Na(v)1.7 antagonists. Hit-to-lead SAR studies of the pyrrolopyrimidine core, head, and tail groups of the molecule led to the identification of pyrrolopyrimidine 48 as exceptionally potent Na(v)1.7 blocker with good selectivity over hERG and improved microsomal stability relative to our hit molecule and pyrazolopyrimidine 8 as a promising starting point for future optimization efforts.     

Phylogenetic position of the acariform mites: sensitivity to homology assessment under total evidence

Background  

Mites (Acari) have traditionally been treated as monophyletic, albeit composed of two major lineages: Acariformes and Parasitiformes. Yet recent studies based on morphology, molecular data, or combinations thereof, have increasingly drawn their monophyly into question. Furthermore, the usually basal (molecular) position of one or both mite lineages among the chelicerates is in conflict to their morphology, and to the widely accepted view that mites are close relatives of Ricinulei.     

AlphaB-crystallin and breast cancer: role and possible therapeutic strategies

AlphaB-crystallin (HSPB5) is one of the most prominent and well-studied members of the small heat shock protein (sHsp) family. To date, it is known that this protein modulates significant cellular processes and therefore, it is not surprising that its deregulation is involved in various human pathologies, including cancer diseases. Despite the pathogenic significance of HSPB5 in cancer and its regulatory mechanism related to aggressiveness is poorly understood, several reports describe the association of breast carcinoma progression with HSPB5, whose expression is also considered an independent predictor of breast cancer metastasis to the brain. Indeed, numerous authors indicate HSPB5 as a new valuable biomarker for clinicopathological parameters and poor prognosis in breast cancer. Considering the cytoprotective, anti-apoptotic, pro-angiogenic, and pro-metastatic properties of the sHsps, it is not surprising that they are considered as promising targets for anticancer treatment, even though, at present, a deeper understanding of their mode of action is needed to allow the development of precise therapeutic interventions. Data on the direct inhibition of different sHsps demonstrate promising results in cancer pathologies; however, specific strategies against HSPB5 have not been considered. This review highlights the most relevant findings on HSPB5 and its role in breast cancer, as well as the possible strategies in using HSPB5 inhibition for therapeutic purposes.     

The role of αB-crystallin in skeletal and cardiac muscle tissues

All organisms and cells respond to various stress conditions such as environmental, metabolic, or pathophysiological stress by generally upregulating, among others, the expression and/or activation of a group of proteins called heat shock proteins (HSPs). Among the HSPs, special attention has been devoted to the mutations affecting the function of the αB-crystallin (HSPB5), a small heat shock protein (sHsp) playing a critical role in the modulation of several cellular processes related to survival and stress recovery, such as protein degradation, cytoskeletal stabilization, and apoptosis. Because of the emerging role in general health and disease conditions, the main objective of this mini-review is to provide a brief account on the role of HSPB5 in mammalian muscle physiopathology. Here, we report the current known state of the regulation and localization of HSPB5 in skeletal and cardiac tissue, making also a critical summary of all human HSPB5 mutations known to be strictly associated to specific skeletal and cardiac diseases, such as desmin-related myopathies (DRM), dilated (DCM) and restrictive (RCM) cardiomyopathy. Finally, pointing to putative strategies for HSPB5-based therapy to prevent or counteract these forms of human muscular disorders.     

Use of the canonical discriminant analysis to select SNP markers for bovine breed assignment and traceability purposes

Several market research studies have shown that consumers are primarily concerned with the provenance of the food they eat. Among the available identification methods, only DNA‐based techniques appear able to completely prevent frauds. In this study, a new method to discriminate among different bovine breeds and assign new individuals to groups was developed. Bulls of three cattle breeds farmed in Italy – Holstein, Brown, and Simmental – were genotyped using the 50K SNP Illumina BeadChip. Multivariate canonical discriminant analysis was used to discriminate among breeds, and discriminant analysis (DA) was used to assign new observations. This method was able to completely identify the three groups at chromosome level. Moreover, a genome‐wide analysis developed using 340 linearly independent SNPs yielded a significant separation among groups. Using the reduced set of markers, the DA was able to assign 30 independent individuals to the proper breed. Finally, a set of 48 high discriminant SNPs was selected and used to develop a new run of the analysis. Again, the procedure was able to significantly identify the three breeds and to correctly assign new observations. These results suggest that an assay with the selected 48 SNP could be used to routinely track monobreed products.