A5025692266- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cytokine Signaling Pathways and Interactions
- Psoriasis: Treatment and Pathogenesis
- IL-33, ST2, and ILC Pathways
- Cannabis and Cannabinoid Research
- NF-κB Signaling Pathways
- Pain Mechanisms and Treatments
- Crystallography and molecular interactions
- Inflammatory mediators and NSAID effects
- Cardiac Arrhythmias and Treatments
- Drug Transport and Resistance Mechanisms
- Congenital Heart Disease Studies
- Advanced Computing and Algorithms
- Immune Response and Inflammation
- Pharmacological Receptor Mechanisms and Effects
- Vascular anomalies and interventions
- Cardiomyopathy and Myosin Studies
- Bioactive Compounds and Antitumor Agents
- Inflammatory Bowel Disease
- Neuroscience and Neuropharmacology Research
- Synthesis and biological activity
- Neurotransmitter Receptor Influence on Behavior
- Receptor Mechanisms and Signaling
- Synthesis and Biological Evaluation
Takeda (Japan)
2012-2019
Kanagawa Cardiovascular and Respiratory Center
1991
A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity tetrahydroisoquinoline compound 1 by replacement trimethylsilyl group SBDD-guided scaffold exchange, which successfully afforded 7 with a lower log D value tolerable in vitro activity. Consideration LLE values subsequent optimization carboxylate tether led to discovery [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1...
G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled receptor. GPR52 inhibits dopamine D2 signaling and activates D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, therefore, agonists may have potential as a novel class of antipsychotics. A series with bicyclic core was designed to fix the conformation phenethyl ether moiety compounds 2a 2b. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N-(2-methoxyethyl)benzamide 7m showed potent activity (pEC50 = 7.53 ±...
Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation Th17 cells and Tc17 cells. Herein, we describe structure-based functionality switching approach from in house well-optimized RORγt inverse potent agonists. We succeeded the identification agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed helix...
<b><i>Background/Aims:</i></b> Retinoid-related orphan receptor gamma t (RORγt) is a master regulator of T helper 17 cells that plays pivotal role in the production inflammatory cytokines including interleukin (IL)-17. Therefore, RORγt has attracted much attention as target for treatment diseases rheumatoid arthritis, multiple sclerosis, bowel diseases, and psoriasis. This study aims to characterize TAK-828F, potent selective inverse agonist....
Retinoic-acid-related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 with flexible linear linker as RORγt agonist. A U-shaped conformation in complex structure protein was confirmed. Further improvement pharmacokinetic (PK) profiles required because low drug exposure mice upon oral administration (mouse AUC a: 27 ng ⋅ h mL-1 at mg kg-1 , p.o.). To improve PK profiles, conformationally...
A case of impending rupture multiple peripheral aneurysm could be successfully managed with prosthetic graft replacement. The was a 76-year-old male complaining pulsatile tumor in the right inguinal region pain. Another tumors were found left and popliteal fossa, namely patient suffered from aneurysm. femoral accompanied by remarkable tenderness diagnosed as rupture. Pulsation palpable arteries both lower extremities. In surgery two-step approach employed. At first step, aneurysms excised,...