A5068350969- Receptor Mechanisms and Signaling
- Diabetes Treatment and Management
- Pancreatic function and diabetes
- Neuropeptides and Animal Physiology
- Pharmacological Effects and Toxicity Studies
- Wood Treatment and Properties
- Antibiotics Pharmacokinetics and Efficacy
- Multiple Myeloma Research and Treatments
- Erythropoietin and Anemia Treatment
- RNA Interference and Gene Delivery
- Cholesterol and Lipid Metabolism
- Chronic Lymphocytic Leukemia Research
- Urinary Bladder and Prostate Research
- Nerve injury and regeneration
- Virus-based gene therapy research
- Drug Transport and Resistance Mechanisms
- Cardiac Ischemia and Reperfusion
- Urinary Tract Infections Management
- Chronic Myeloid Leukemia Treatments
- Biosimilars and Bioanalytical Methods
- Molecular Sensors and Ion Detection
- Estrogen and related hormone effects
- Structural Behavior of Reinforced Concrete
- HIV/AIDS drug development and treatment
Biogen (United States)
2023-2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2016-2019
AstraZeneca (United Kingdom)
1996
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), nonreceptor member of the TEC family kinases, involved in regulation, migration, functional activation B cells myeloid periphery central nervous system (CNS), cell types which are deemed to contributing progression MS patients. Herein, we describe discovery BIIB129 (25), structurally distinct...
Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe effective insulin sensitizers, absent weight gain, has been a long-standing goal research. G-protein coupled receptor 120 (GPR120) recently emerged as potential therapeutic target for treating T2DM. Natural occurring, more recently, synthetic agonists have associated with sensitizing, anti-inflammatory, fat metabolism effects. Herein we describe design, synthesis, evaluation novel...
GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been target of significant recent therapeutic interest for type II diabetes. Activation by partial agonists elicits insulin secretion only the presence elevated blood glucose levels, minimizing risk hypoglycemia. agoPAMs have shown superior efficacy to as assessed tolerability test (GTT). Herein, we report discovery optimization series potent, selective agoPAMs. Compound 24...
GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as target for possible treatment of type 2 diabetes. A selective activator containing chromane scaffold designed, synthesized, and evaluated in vivo. Results these efforts suggest propionic 18 suitable tool molecule further animal studies. Compound over the closely related GPR40 (FFAR1), clean off-target profile, demonstrates pharmacokinetic properties, wild-type/knockout mouse oGTT
Recombinant adeno-associated virus (AAV)-mediated degeneration of sensory neurons in the dorsal root ganglia (DRG) and trigeminal (TG) has been observed non-human primates (NHPs) following intravenous (IV) intrathecal (IT) delivery. Administration recombinant AAV encoding a human protein transgene via single intra-cisterna magna (ICM) injection New Zealand white rabbits resulted histopathology changes very similar to NHPs: mononuclear cell infiltration, degeneration/necrosis neurons, nerve...
GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell increase stimulated insulin secretion. However, not all same. Partial pancreas, whereas AgoPAMs may incorporate additional therapeutic increases in insulinotrophic incretins secreted by gut. Here we describe how stimulate both and incretin secretion vivo over time diabetic GK rats. We also of body weight beyond what is seen with partial acute chronic setting. Further comparisons...
GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class triazole agonists was discovered through high throughput screen. The lead compound 4 suffered from poor metabolic stability and solubility. Lead optimization strategies to improve potency, efficacy, stability, solubility are described. This led 20e, which showed significant reduction glucose excursion in wild-type but not deficient mice an...
GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects vivo. Several reports illustrate that agonists exert diabetic humans. To assess the mechanisms by which partial improve homeostasis, we evaluated of MK-2305, selective agonist, Goto Kakizaki rats. MK-2305 decreased fasting after acute chronic treatment. MK-2305-mediated changes were coupled with increases plasma insulin during hyperglycemia challenges but not fasting, when was...
A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class channel openers (PCOs). structure−activity relationship was carried out on western region this series with goal obtaining an activator suitable for use in treatment urge urinary incontinence. In particular three large 4-(N-aryl) substituents, (N-phenyl-N-methylamino)sulfonyl, benzoyl, 4-pyridylsulfonyl...
A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation endogenous ligands (AgoPAM) were discovered as potential therapeutics treatment type II diabetes. Optimization physicochemical properties through modification pendant aryl rings resulted in identification compound AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.
Capillary microsampling (CMS) is a technique that can significantly reduce the blood collection volume compared to conventional sampling methods, and thus much preferred for studies in rats mice. BIIB131 (SMTP-7) novel thrombolytic drug candidate currently under Phase 2 clinical development treatment of acute ischemic stroke. To support safety rats, an accurate reliable CMS LC-MS/MS assay quantification rat plasma was developed validated. This method utilized stable-isotope labeled...