A5079713627- Sleep and Wakefulness Research
- Sleep and related disorders
- Circadian rhythm and melatonin
- Pulmonary Hypertension Research and Treatments
- Photochromic and Fluorescence Chemistry
- Nitric Oxide and Endothelin Effects
- Sphingolipid Metabolism and Signaling
- Neuroscience and Neuropharmacology Research
- Mycobacterium research and diagnosis
- Crystallization and Solubility Studies
- Tuberculosis Research and Epidemiology
- Eicosanoids and Hypertension Pharmacology
- Immune Cell Function and Interaction
- X-ray Diffraction in Crystallography
- Ion channel regulation and function
- Immunotherapy and Immune Responses
- Crystallography and molecular interactions
- Monoclonal and Polyclonal Antibodies Research
- Cardiovascular Issues in Pregnancy
- Immune Response and Inflammation
- Receptor Mechanisms and Signaling
- PI3K/AKT/mTOR signaling in cancer
- Advanced biosensing and bioanalysis techniques
- Cell Adhesion Molecules Research
- Fluorine in Organic Chemistry
Idorsia (Switzerland)
2017-2025
Idera Pharmaceuticals (United States)
2021
Actelion (Switzerland)
2008-2017
Centre for Human Drug Research
2017
University of Basel
2002-2008
Cornell University
2005
University of British Columbia
2005
University of Tübingen
1998-1999
Mycobacteria are intracellular pathogens that can invade and survive within host macrophages, thereby creating a major health problem worldwide. The molecular mechanisms involved in mycobacterial entry still poorly characterized. Here we report cholesterol is essential for uptake of mycobacteria by macrophages. Cholesterol accumulated at the site entry, depleting plasma membrane specifically inhibited uptake. also mediated phagosomal association TACO, coat protein prevents degradation...
Macitentan, also called Actelion-1 or ACT-064992 [<i>N</i>-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-<i>N</i>′-propylaminosulfonamide], is a new dual ET<sub>A</sub>/ET<sub>B</sub> endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency both ET receptors and optimization physicochemical properties to achieve high affinity lipophilic milieu. In vivo, metabolized into major pharmacologically...
Chemotherapeutic options to treat tuberculosis are severely restricted by the intrinsic resistance of Mycobacterium majority clinically applied antibiotics. Such is partially provided low permeability their unique cell envelope. Here we describe a complementary system that coordinates drugs have penetrated envelope, allowing mycobacteria tolerate diverse classes antibiotics inhibit cytoplasmic targets. This depends on whiB7 , gene pathogenic shares with Streptomyces phylogenetically related...
Abstract The tert ‐butyl group is a common motif in medicinal chemistry. Its incorporation into bioactive compounds often accompanied by unwanted property modulation, such as increased lipophilicity and decreased metabolic stability. Several alternative substituents are available for the drug discovery process. Herein, physicochemical data of two series analogues bosentan vercirnon documented part comparative study ‐butyl, pentafluorosulfanyl, trifluoromethyl, bicyclo[1.1.1]pentanyl,...
Sphingosine-1-phosphate (S1P) is a widespread lysophospholipid which displays wealth of biological effects. Extracellular S1P conveys its activity through five specific G-protein coupled receptors numbered S1P(1) S1P(5). Agonists the receptor block egress T-lymphocytes from thymus and lymphoid organs hold promise for oral treatment autoimmune disorders. Here, we report on discovery detailed structure-activity relationships novel class agonists based 2-imino-thiazolidin-4-one scaffold....
Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated system aberrant contraction proliferation smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in Phase III morbidity/mortality clinical trial PAH patients. Since association dissociation rates G protein-coupled can influence their pharmacological activity vivo, we...
Coronin 1 is a member of the coronin protein family specifically expressed in leukocytes and accumulates at sites rearrangements F-actin cytoskeleton. Here, we describe that molecules are coiled coil-mediated homotrimeric complexes, which associate with plasma membrane cytoskeleton via two distinct domains. Association was mediated by trimerization stretch positively charged residues within linker region between N-terminal, WD repeat-containing domain C-terminal coil. In contrast, neither...
ABSTRACT While in most rod-shaped bacteria, morphology is based on MreB-like proteins that form an actin-like cytoskeletal scaffold for cell wall biosynthesis, the factors determine more flexible rod-like shape actinobacteria such as Mycobacterium species are unknown. Here we show a smegmatis protein homologous to eubacterial DivIVA-like proteins, including M. tuberculosis antigen 84 (Ag84), localized symmetrically centers of peptidoglycan biosynthesis at poles and septa. Controlled gene...
Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that orally available, penetrates the brain, decreases fear, compulsive behaviors autonomic reactions in rats.
Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased production occurs in several diseases. However, clinical use and its analogues is complicated by their chemical metabolic instability. A medicinal chemistry program searched for novel nonprostanoid receptor agonists not subject to these limitations. compound with a diphenylpyrazine structural core was synthesized. Metabolic stability agonist potency were optimized through modification linear...
The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset action, maintenance throughout major parts the night, and absence residual next-day effects. Robust tools estimate levels human brain are therefore key for a successful program. Animal models constitute an appropriate choice without species differences receptor pharmacology or pharmacokinetics. Translation man becomes more challenging when...
The orexin system consists of two neuropeptides (orexins A and B) receptors (OX1 OX2). Selective OX1 receptor antagonists (SO1RA) are gaining interest for their potential use in the treatment CNS disorders, including substance abuse, eating, obsessive compulsive, or anxiety disorders. While blocking OX2 reduces wakefulness, expected advantage selectively antagonizing is ability to achieve clinical efficacy without promotion sleep. Herein we report our discovery efforts starting from a dual...
Idiopathic pulmonary fibrosis is a life-threatening progressive disease characterized by loss of alveolar epithelial cells, inflammation, and aberrant fibroblast activation. The two currently approved therapies do not halt or reverse tissue remodeling, therefore novel disease-modifying mechanisms are needed. Our results describe YAP/TAZ inhibition through prostacyclin (IP) receptor activation as mechanism that suppresses profibrotic (myo)fibroblast activity. We investigated the antifibrotic...
Abstract Since its discovery in 1998, the orexin system has been of interest to research community as a potential therapeutic target for treatment sleep/wake disorders, stress and anxiety addiction or eating disorders. It consists two G protein‐coupled receptors, 1 2 neuropeptides with agonistic effects, A B peptides. Herein we describe our efforts leading identification promising set dual receptor antagonists (DORAs) which subsequently went through physiology‐based pharmacokinetic...
Three distinct pharmacological corrector types (I, II, III) with different binding sites and additive behavior only partially rescue the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding trafficking defect observed in cystic fibrosis. We describe uniquely effective, macrocyclic CFTR correctors that were to known types, exerting a complementary “type IV” mechanism. Macrocycles achieved wild-type–like efficiency of F508del-CFTR at endoplasmic reticulum normalized...
Macrophages are crucial for innate immunity, apoptosis, and tissue remodeling, processes that rely on the capacity of macrophages to internalize process cargo through phagocytosis. Coronin 1, a member WD repeat protein family coronins specifically expressed in leukocytes, was originally identified as molecule is recruited mycobacterial phagosomes prevents delivery mycobacteria lysosomes, allowing these survive within phagosomes. However, role coronin 1 pathogenesis has been disputed favor...
The orexin system consists of two G-protein-coupled receptors, the 1 and 2 widely expressed in diverse regions brain, peptide agonists, A B, which are produced a small assembly neurons lateral hypothalamus. plays an important role maintenance wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been advanced clinical trials for treating primary insomnia. ACT-462206 is new, potent, selective dual receptor antagonist (DORA) that inhibits stimulating effects peptides at both...
FTY720 phosphate (FTY720-P; 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol, monodihydrogen ester) is a nonselective sphingosine-1-phosphate (S1P) receptor agonist thought to be devoid of activity at the S1P2 subtype. However, we have recently shown that FTY720-P displays significant in recombinant cells and fibroblasts expressing endogenous receptors. To elucidate S1P2-dependent signaling pathways were activated by FTY720-P, employed second messenger assays impedance-based combination...
Prostacyclin (PGI2) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit vasoconstriction, smooth muscle cell (PASMC) proliferation, extracellular matrix synthesis. Selexipag (Uptravi, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide) is first nonprostanoid IP agonist, it available orally was recently approved PAH. In this study we show that...
Tissue fibrosis is a pathological condition characterized by uncontrolled fibroblast activation that ultimately leads to organ failure. The TGFβ1 pathway, one of the major players in establishment disease phenotype, dependent on transcriptional co-activators YAP/TAZ. We were interested whether fibroblasts can be sensitized GPCR/YAP/TAZ axis and this mechanism explains profibrotic properties diverse GPCR ligands. found LPA, S1P thrombin cooperate human dermal with induce extracellular matrix...