A5082836367- Nausea and vomiting management
- Regulation of Appetite and Obesity
- HIV/AIDS drug development and treatment
- Anesthesia and Sedative Agents
- Biochemical Analysis and Sensing Techniques
- Hepatitis C virus research
- Glioma Diagnosis and Treatment
- Chemical Synthesis and Reactions
- Hepatitis B Virus Studies
- Synthetic Organic Chemistry Methods
- Anesthesia and Pain Management
- Adipose Tissue and Metabolism
- Adipokines, Inflammation, and Metabolic Diseases
- Cutaneous lymphoproliferative disorders research
- Nail Diseases and Treatments
- Lung Cancer Treatments and Mutations
- Adenosine and Purinergic Signaling
- Asymmetric Synthesis and Catalysis
- Oxidative Organic Chemistry Reactions
- RNA modifications and cancer
- Asymmetric Hydrogenation and Catalysis
- Chromatin Remodeling and Cancer
- Genetic and rare skin diseases.
- Chemical Synthesis and Analysis
- Hypothalamic control of reproductive hormones
Helsinn (Switzerland)
2013-2023
Hertie Institute for Clinical Brain Research
2022
German Center for Neurodegenerative Diseases
2022
University of Tübingen
2022
Bioscience (China)
2018
University of Oklahoma Health Sciences Center
2018
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010-2011
IRBM Science Park
2005-2009
University of Basilicata
1992-1993
Sapienza University of Rome
1992
Abstract RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of limited, however, acquired mutations the drug target as well brain metastasis, presumably due to inadequate penetration. Here, we perform preclinical characterization...
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies in urgent demand. Compounds that block replication of subgenomic HCV RNA liver cells interest because their demonstrated antiviral effect the clinic. In followup to our recent report indole-N-acetamides (e.g., 1) potent allosteric inhibitors NS5B polymerase enzyme, we describe here optimization as cell-based inhibitors. The crystal structure 1 bound was guide design two-dimensional...
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies in urgent demand. The polymerase of HCV is responsible the replication viral genome and has been prime target drug discovery efforts. Here, we report on further development tetracyclic indole inhibitors, binding to an allosteric site thumb domain. Structure−activity relationship (SAR) studies around indolo-benzoxazocine scaffold led identification compound 33 (MK-3281), inhibitor...
Abstract Netupitant is a new, selective NK 1 receptor antagonist under development for the prevention of chemotherapy‐induced nausea and vomiting. Two studies were conducted to evaluate brain occupancy (RO) disposition (ADME) netupitant in humans. Positron emission tomography (PET) imaging with receptor‐binding–selective tracer [ 11 C]‐GR205171 was used penetration different doses (100, 300, 450 mg) determine ‐RO duration. A 90% or higher achieved all majority tested regions at C max, long...
Abstract Background Constipation and L‐dopa‐induced gastric dysmotility are common gastrointestinal ( GI ) symptoms in P arkinson's disease PD ). We investigated the novel ghrelin agonist, HM 01 influence on motor dysfunctions 6‐hydroxydopamine (6‐ OHDA rats. Methods pharmacological profiles were determined vitro vivo assessed changes fecal output water content, emptying GE 6‐ rats treated with orogastric (og) L‐dopa/carbidopa LD / CD , 20/2 mg/kg). Fos immunoreactivity (ir) cells specific...
Aims Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand‐independent constitutive activity, which can be pharmacologically exploited to induce inverse actions. Because agonists ( GHSR ‐ IA ) might effective for treatment obesity‐related metabolic disease, we tested 2 novel synthetic compounds 1 2. Materials Methods In functional cell assays, electrophysiogical immunohistochemical experiments, demonstrated agonist activity We...
The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral with the non-peptidergic receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. C26 tumor model is characterized by pronounced body weight (BW) loss muscle wasting absence of severe anorexia. We analyzed time course BW loss, composition, mass,...
The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to characterize the action of nonpeptidergic receptor agonist HM01 on neuronal function, homeostasis muscle mass in healthy rats evaluate its usefulness for CACS rat tumor model. Using extracellular single-unit recordings, we tested whether mimics effects activity arcuate...
A very accurate and selective LC-MS/MS method was developed validated for the quantification of 2'-C-modified nucleoside triphosphate in liver tissue samples. An efficient pretreatment procedure samples developed, using a fully automated SPE with 96-well plate (weak anion exchange sorbent, 30 mg). Nucleotide hydrophilic interaction chromatography has been performed on an aminopropyl column (100 mm x 2.0 mm, 3 microm) gradient mixture ACN ACN/water (5:95 v/v) 20 mM ammonium acetate at pH 9.45...
Chemotherapy-induced acute and delayed emesis involves the activation of multiple pathways, with 5-hydroxytryptamine (5-HT; serotonin) playing a major role in initial response. Substance P tachykinin NK1 receptor antagonists can reduce induced by disparate emetic challenges therefore have clinical utility as broad inhibitory anti-emetic drugs. In present studies, we investigate profile relatively new antagonist, netupitant, alone or combination long acting 5-HT3 palonosetron, for potential...
Abstract several epoxides and epoxy alcohols have been opened to the corresponding halohydrins by lithium halides with Amberlyst in CH3CN at room temperature: reaction proceeds quantitative yields high degree of regioselectivity.
Ghrelin has well-known activity to stimulate appetite and weight gain. Evidence suggests that ghrelin may also have useful effects in reducing chemotherapy-induced emesis via growth hormone secretagogue receptors (GHS-R1A) the brain. However, it is not known whether stimulation of GHS-R1A broad inhibitory anti-emetic effects. In present studies, we used Suncus murinus investigate potential new novel orally bioavailable brain-penetrating mimetic, HM01...
A new chemotype of ghrelin inverse agonists was discovered through chimeric design based on molecular scaffolds known as growth-hormone secretagogue receptor (GHSR) modulators but with divergent pharmacodynamic and pharmacokinetic properties. The structure-activities/properties exploration led to compound 47, which displayed potent human GHSR antagonism agonism in cellular assays (IC50 = 68 nM, EC50 29 nM), moderate oral bioavailability, notable brain penetration rat ( F 27%, B/ P ratio...
2024 Background: Patients with RET fusion-positive NSCLC have an estimated 25% incidence of CNS metastasis at diagnosis, and up to 40% during disease progression. Effective anti-RET therapy that penetrates the blood-brain barrier is essential extending survival. TAS0953/HM06 a structurally distinct RET-specific inhibitor exhibits binding mode effective against solvent front (G810) gatekeeper (V804) mutations. also inhibits growth xenograft tumors established from fusion-driven multiple...
HM01, a novel, orally bioavailable, brain-penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that the less receptor agonist, HM02.The potential HM01 and HM02 to relax isolated mesenteric arteries increase feeding was investigated. Radio telemetry used record gastric slow waves body temperature. Plethysmography measure respiratory function. were administered p.o. 1 hr prior provocative motion, c-Fos...
Oral NEPA is the fixed-combination antiemetic comprising netupitant (neurokinin-1 receptor antagonist [NK1 RA]) and palonosetron (5-hydroxytryptamine-3 [5-HT3 RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water-soluble N-phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK1 RA water solubility, preventing occurrence hypersensitivity infusion-site reactions associated with these...
The gastrointestinal (GI) prokinetic effects of ghrelin occur through direct peripheral on receptors within the enteric nervous system and via receptor vagus nerve, which activate a centrally mediated mechanism. However, relative contribution versus central to overall effect agonists requires further investigation. Here, we investigated by using two novel agonists: HM01...
The DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis fungoides cutaneous T-cell lymphoma, with positive benefit/risk ratio. Release profiles of from the and compounded ointment-based formulation were compared via vitro release testing (IVRT), utilizing static diffusion cells, pseudo-infinite dose, polytetrafluoroethylene membranes, over 5 h. percutaneous absorption profile ex...
Abstract Fusions involving RET receptor tyrosine kinase are a common driver of tumors across different tissue types, such as lung, thyroid, colorectal, soft and others. TAS0953/HM06 (hereby referred to HM06) is novel 2ndgeneration RET-specific inhibitor that effective against solvent front (G810) gatekeeper (V804) mutations. Here, we evaluated the efficacy HM06 in lung thyroid carcinomas, soft-tissue sarcoma cell lines PDXs derived from inhibitor-naive tumor samples or with acquired...