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Patented Farnesoid X receptor modulators: a review (2019 – present)
No full textIntroductionThe Farnesoid X receptor (FXR) is a key transcription factor that is involved in the bile acid signaling network. The modulation of the FXR activity influences glucose and lipid homeostasis, reduces obesity and insulin resistance, as well as it regulates the pathogenesis of inflammatory and metabolic disorders. FXR ligands have therefore emerged in drug discovery as promising therapeutic agents for the prevention and treatment of gastrointestinal and liver diseases, including cancer.Areas coveredRecent advances in the field of FXR modulators are reviewed, with a particular attention on patent applications filed in the past 5 years related to both the discovery and development of FXR targeting drugs.Expert OpinionFXR agonists have proven their efficacy and safety in humans and have shown a significant potential as clinical agents to treat metabolic and inflammatory associated conditions. However, several challenges, including adverse events such as pruritus, remain to be solved. Current studies aim to gain insights into the pathophysiological mechanisms by which FXR regulates metabolism and inflammation in terms of tissue/organ/isoform-specificity, post-translational modifications and coregulatory proteins, on the route of novel, improved FXR modulators
Integrating Multicomponent Flow Synthesis and Computational Approaches for the Generation of a Tetrahydroquinoline Compound Based Library
No full textThe combination of flow chemistry and computational tools has been successfully applied to prepare a focused library of tricyclic tetrahydroquinolines endowed with drug-like properties. The study illustrates the efficient synthesis of this class of compounds using flow mesoreactors in a multicomponent fashion, as well as the profitable employment of computational chemistry for library diversity analysis. Early biological characterization of selected compounds of the library are also presented for the discovery of novel chemical probes to unravel estrogen receptor signaling pathways
Concepts and optimization strategies of experimental design in continuous-flow processing
No full textThe integration of flow systems with statistical design of experiments is emerging as a valuable strategy to develop new synthetic routes towards relevant building blocks, chemical probes, and drug compounds. Optimization by experimental design incorporates statistical algorithms, mathematical models and equations, predicting tools, feedback control, and validation to generate new optimal conditions. Continuous-flow chemistry is ideally suited for this scope, as the integration of in-line analysis is simple; experimental parameters such as temperature, pressure, and flow rate can be easily controlled and fine-regulated; and automation of reaction screening can be accomplished with software assistance. This review article aims to illustrate how the combination of flow synthesizers and design of experiments can be profitable to speed up the development and optimization of more efficient, safer, and reproducible protocols for modern synthetic methods and manufacturing processes
Beyond Bile Acids: Targeting Farnesoid X Receptor (FXR) with Natural and Synthetic Ligands
No full textThe modulation of FXR receptor remains an attractive area in drug discovery to develop novel
therapeutic opportunities for liver and metabolic disorders. Despite the large variety of FXR ligands reported
so far, only a very restricted number of agonists have entered in clinical settings. In this review article we provide
the reader with an overview on the different classes of natural and synthetic ligands that have been developed
by academic groups and pharmaceutical companies to target FXR. We discuss their structure-activity relationships,
analyzing the binding modes that some of these compounds adopt to interact with the receptor
ATYPICAL BILE ACIDS AS CHEMICAL PROBES FOR DIAGNOSIS AND THERAPHY MONITORING OF PROGRESSIVE CHOLESTATIC LIVER DISEASE IN HSD3B7 PATIENTS
No full textInborn errors in bile acid synthesis are a well-recognized category of metabolic liver disease. These autosomal recessive genetic defects manifest as a broad phenotype presenting with an overlapping spectrum of variable degrees of neonatal cholestasis, fat-soluble vitamin malabsorption, and neuropathies. 3b-Hydroxy-D5-C27-steroid oxidoreductase (HSD3B7) deficiency is the most common of the 9 known defects in bile acid biosynthesis and is often the cause of idiopathic forms of late-onset chronic cholestasis in children and adolescents, and even in adult. Early diagnosis of these genetic defects is crucial to prognosis, because if undiagnosed or untreated, the liver disease, which is a progressive form of intrahepatic cholestasis, leads to fibrosis, cirrhosis, and end-stage disease. Treatment options include liver transplantation or preferably oral bile acid therapy with the primary bile acids, cholic or chenodeoxycholic acids. Diagnosis of HSD3B7 deficiency is based on the detection of increased concentrations of atypical 3-hydroxy-D5-bile acids that accumulate in urine because of the lack of enzyme activity caused by mutations in HSDB7 gene. So far, direct and accurate measurement of these conjugated 3b-hydroxy-D5-bile acids has not been possible for the lack of reference standards.
We describe here the synthesis and bio-chemical characterization of a series of D5-cholenoic acid analogs, which are the signature metabolites of the HSD3B7 deficiency in humans. Using these synthesized compounds as tools to gain insights into the mechanism(s) responsible of the cholestasis and liver damage in patients with the HSD3B7 deficiency, we report their cellular hepatocytotoxicity, their affinity towards a subset of bile acid-responsive nuclear receptors and the effects on genes and cytochromes involved in bile acid homeostasis and detoxification. Moreover, the availability of these reference compounds has allowed developing an electrospray ionization (ESI) LC-MS/MS method for the accurate measurement of their concentrations in clinical diagnosis and monitoring of response to therapy in patients with HSD3B7 deficiency
Speeding up Early Phases of Drug Discovery: DoE-Driven Synthetic Optimization of Chemical Processes in Flow Systems
No full textIn recent years, medicinal and synthetic chemistry have experienced a significant evolution in the approaches used and general thinking. Several research groups from both academia and within pharmaceutical companies have adopted more technological solutions to help the delivery of compounds from early phases of discovery to (pre)clinical investigations and drug production. Modern chemical manufacturing companies and academic laboratories are investing resources to drive a radical innovation in synthetic technologies, which would enable the conduction of chemical transformations that are difficult or impossible to be realized because of safety restriction, timing, costs, and environmental impact. Within this changing landscape, flow chemistry has rapidly emerged as a key technique that can significantly support these efforts leading to a radical change on how chemists think, perform and optimize chemical synthesis.
In this communication, we have combined the potentiality of flow systems with automated equipment and software for the generation of compounds library and lead candidates advanced in preclinical settings of ischemia and cancer. In particular, the profitable use of statistical design of experiments (DoE) will be demonstrated as a valuable tool to understand the benefits and risks associated with the chemical process and to speed up the synthetic optimization through a careful selection of experiments and the interpretation and validation of the results obtained
IDENTIFICATION OF A NOVEL CLASS OF PREGNANE X RECEPTOR (PXR) LIGANDS: FLOW SYNTHESIS AND PRELIMINARY BIOLOGICAL ACTIVITY OF TETRAHYDROQUINOLINES
No full textDiscovered in 1998 as a member of ligand-activated transcription factors, Pregnane X Receptor (PXR, NR1I2) plays a key role in metabolic detoxification systems by sensing the presence of xenobiotics and triggering detoxification responses. Moreover, PXR regulates immune/inflammatory responses, cell proliferation, bile acid/cholesterol homeostasis, glucose and lipid metabolism, and steroid/endocrine homeostasis. Recent findings suggest that PXR is also required for maintaining healthy commensalism between microbiota and gut. In view of the multiple roles in various physiological processes, targeting PXR in relevant human diseases represents one of the most promising and challenging approaches for developing novel therapeutic strategies. To validate PXR as clinically relevant and druggable target, it is therefore crucial to discover and develop small molecules that specifically bind and modulate PXR-mediated pathways.
As a continuation of our ongoing research programmes towards the development of steroid-responsive nuclear receptor modulators,3 herein we report the design and implementation of a multicomponent flow-assisted synthesis for the preparation of a focused library of tetrahydroquinolines. Moreover, the preliminary results of in vitro biological evaluations of the synthesized compounds as PXR ligands will be also reported and discussed
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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