The Discovery of Nonpeptide Endothelin Receptor Antagonists. Progression towards Bosentan

Since its discovery, endothelin-1 has attracted considerable scientific interest for its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. The endothelins appear to be part of a functional regulatory system in the circulation and strong evidence has accumulated for their involvement in clinical disorders associated with vasoconstriction (e.g. renal failure, congestive heart failure).In a program aimed at identifying nonpeptide ET receptor antagonists, a distinct class of substituted arylsulfonamido pyrimidines was discovered from a chemical substance library. Lead optimization led to orally active antagonists of ETA and ETB receptors possessing mixed or receptor-subtype-selective profiles in the low nanomolar range. From these compounds, the mixed antagonist bosentan was selected for development; it shows efficacy in several pathophysiological models of local and systemic vasoconstriction and promising clinical results in patients suffering from congestive heart failure.Chemical modifications in this structural class in combination with X-ray crystal data analysis for key compounds led to more in-depth understanding of antagonist-receptor interaction. Structural determinants of bosentan binding to the ETA receptor were defined on the molecular level by site-directed mutagenesis experiments. This led to a 3D model of the antagonist binding domain which proved valuable to rationalize structure-activity relationships

Challenges and Rewards in Medicinal Chemistry Targeting Cardiovascular and Metabolic Diseases

Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11?-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes

Frontiers in Medicinal Chemistry – Joint German-Swiss Meeting on Medicinal Chemistry: Heidelberg, Germany, March 15–18, 2009: Conference Report

'Frontiers in Medicinal Chemistry 2009' was organized as a joint German-Swiss meeting at the University of Heidelberg. It covered the areas of kinases and nuclear hormone receptors, inflammatory diseases, atherosclerosis and neuropsychiatry. Special sessions were dedicated to new technologies in nanomedicine, proteomics and drug targeting. A session on highlights in medicinal chemistry completed the program. The lectures covered a broad range of interdisciplinary topics including molecular design and lead optimization programs, development and application of new technologies in proteomics, drug delivery & chemical synthesis

Frontiers in Medicinal Chemistry – Joint German-Swiss Meeting on Medicinal Chemistry: Berlin, Germany, March 18–21, 2007: Conference Report

The 2007 congress Frontiers in Medicinal Chemistry was organized as a joint German–Swiss meeting on medicinal chemistry and was held at the Freie Universität Berlin. It focused on the areas of antiinfectives and tropical diseases, CNS disorders and neurodegeneration, and on oncology. Two additional sessions on new technologies and metabolism and on 'highlights' completed the program. The lectures covered a broad range of interdisciplinary topics, defining disease state, applying technologies to screen for pathological targets, molecular design and lead optimization programs, and challenges and aspects of industrial syntheses and process research

Channels and transporters. Mini-symposium of the Division of Medicinal Chemistry (DMC) of the Swiss Chemical Society (SCS) at the Department of Chemistry, University of Basel, May 27, 2010

During a half-day symposium, the topic 'Channels and Transporters' was covered with five lectures, including a presentation on 'Introduction and Basics of Channels and Transporters' by Beat Ernst, lectures on structure, function and physiology of channels and transporters ('The Structural Basis for Ion Conduction and Gating in Pentameric Ligand-Gated Ion Channels' by Raimund Dutzler and 'Uptake and Efflux Transporters for Endogenous Substances and for Drugs' by Dietrich Keppler), and a case study lecture on 'Avosentan' by Werner Neidhart. The program was completed by Matthias Hediger who introduced to the audience the National Center of Competence in Research (NCCR)-TransCure in his lecture entitled 'From Transport Physiology to Identification of Therapeutic Targets'

Correlation of intravascular ultrasound findings with histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis

BACKGROUND: Intravascular ultrasound of drug-eluting stent (DES) thrombosis (ST) reveals a high incidence of incomplete stent apposition (ISA) and vessel remodeling. Autopsy specimens of DES ST show delayed healing and hypersensitivity reactions. The present study sought to correlate histopathology of thrombus aspirates with intravascular ultrasound findings in patients with very late DES ST. METHODS AND RESULTS: The study population consisted of 54 patients (28 patients with very late DES ST and 26 controls). Of 28 patients with very late DES ST, 10 patients (1020+/-283 days after implantation) with 11 ST segments (5 sirolimus-eluting stents, 5 paclitaxel-eluting stents, 1 zotarolimus-eluting stent) underwent both thrombus aspiration and intravascular ultrasound investigation. ISA was present in 73% of cases with an ISA cross-sectional area of 6.2+/-2.4 mm(2) and evidence of vessel remodeling (index, 1.6+/-0.3). Histopathological analysis showed pieces of fresh thrombus with inflammatory cell infiltrates (DES, 263+/-149 white blood cells per high-power field) and eosinophils (DES, 20+/-24 eosinophils per high-power field; sirolimus-eluting stents, 34+/-28; paclitaxel-eluting stents, 6+/-6; P for sirolimus-eluting stents versus paclitaxel-eluting stents=0.09). The mean number of eosinophils per high-power field was higher in specimens from very late DES ST (20+/-24) than in those from spontaneous acute myocardial infarction (7+/-10), early bare-metal stent ST (1+/-1), early DES ST (1+/-2), and late bare-metal stent ST (2+/-3; P from ANOVA=0.038). Eosinophil count correlated with ISA cross-sectional area, with an average increase of 5.4 eosinophils per high-power field per 1-mm(2) increase in ISA cross-sectional area. CONCLUSIONS: Very late DES thrombosis is associated with histopathological signs of inflammation and intravascular ultrasound evidence of vessel remodeling. Compared with other causes of myocardial infarction, eosinophilic infiltrates are more common in thrombi harvested from very late DES thrombosis, particularly in sirolimus-eluting stents, and correlate with the extent of stent malapposition