A5045218076- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Sulfur-Based Synthesis Techniques
- Catalytic C–H Functionalization Methods
- Chemical Synthesis and Reactions
- Pharmacogenetics and Drug Metabolism
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Cancer Treatment and Pharmacology
- Crystallography and molecular interactions
- Urinary Bladder and Prostate Research
- Catalytic Alkyne Reactions
- Drug-Induced Hepatotoxicity and Protection
- Inflammatory mediators and NSAID effects
- Psoriasis: Treatment and Pathogenesis
- Catalytic Cross-Coupling Reactions
- Urinary Tract Infections Management
- NF-κB Signaling Pathways
- Neuroscience and Neuropharmacology Research
- 14-3-3 protein interactions
- Chemical Synthesis and Analysis
- Bioactive Compounds and Antitumor Agents
- Receptor Mechanisms and Signaling
- Aldose Reductase and Taurine
- Estrogen and related hormone effects
Takeda (Japan)
2015-2025
Takeda (United States)
2019-2021
Kyoto University
2004-2010
Shionogi (Japan)
1995-2000
Okayama University
1998
Futaba (Japan)
1998
Allyl cyanides are found to add across alkynes in the presence of a nickel/P(4-CF3−C6H4)3 catalyst give polysubstituted 2,5-hexadienenitriles with defined stereo- and regiochemistry. Use AlMe2Cl or AlMe3 as Lewis acid cocatalyst accelerates reaction expands substrate scope significantly. The cyano group allylcyanation products can be transformed hydroxymethyl aminomethyl afford highly substituted allylic alcohols amines. α-Siloxyallyl also selectively at less hindered γ-carbon allow...
Allyl cyanides are found to add across alkynes in the presence of a nickel catalyst prepared from Ni(cod)2 and P(4-CF3-C6H4)3 situ give variously functionalized di- or trisubstituted acrylonitriles highly stereoselective manners possibly via pi-allylnickel species as an intermediate. alpha-Siloxyallyl also react at gamma-position cyano group with both internal terminal having various functional groups silyl enol ethers, which corresponding aldehydes ketones upon hydrolysis.
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...
Abstract The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances human hepatotoxicity models and improvements reducing liver-related attrition preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II due to the appearance severe DILI. Here, we investigate likely mechanism TAK-994 DILI hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on transporter...
Nickel/Lewis acid dual catalysis was found to effect the carbocyanation reaction of alkynes using arylacetonitriles, giving a range triply substituted acrylonitriles; optically active α-phenylpropionitrile suggested mechanism that involves oxidative addition C–CN bond with retention its absolute configuration.
The role that physicochemical properties play toward increasing the likelihood of toxicity findings in vivo studies has been well reported, albeit sometimes with different conclusions. We decided to understand prediction toxicological outcomes for Takeda chemistry using 284 internal compounds. In support previously reported "3/75 rule", reducing lipophilicity molecules decreases odds noticeably; however, we also found trend is between compounds classified by their ionization state. For basic...
Abstract Nickel/Lewis acid dual catalysis is found to effect the carbocyanation reaction of alkynes using acetonitrile and substituted acetonitriles give a range variously acrylonitriles. The addition propionitrile across also demonstrated briefly corresponding ethylcyanation products in good yields, whereas butyronitrile gives significant amounts hydrocyanation due possibly β-hydride elimination propylnickel intermediate. optically active α-phenylpropionitrile suggests mechanism that...
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...
Palladium-iminophosphine complex catalyzes stannylative cycloaddition of conjugated enynes using hexabutyldistannoxane as a stannylating agent to afford highly substituted 3-alkenylphenylstannanes regioselectively. Stannylative cross-cycloaddition reactions between different or and diynes are also achieved. The reaction is successfully applied concise synthesis alcyopterosin N, which has been isolated recently from sub-Antarctic soft coral, Alcyonium paessleri.
Despite the recent advances in life sciences and remarkable investment drug discovery research, success rate of small-molecule development remains low. Safety is second most influential factor attrition clinical studies; thus, selection compounds with fewer toxicity concerns crucial to increase discovery. Compounds that promiscuously bind multiple targets are likely cause unexpected pharmacological activity may lead adverse effects. Therefore, avoiding such during early research stages would...
Here, we established a high-throughput in vitro assay system to predict reactive metabolite (RM) formation. First, performed the glutathione (GSH) consumption monitor GSH levels as an index of RM formation potential using HepaRG cells pretreated with 500 μM D,L-buthionine-(S,R)-sulfoximine (BSO) and then treated ticlopidine diclofenac. Both drugs, under GSH-reduced conditions, significantly decreased relative cellular content by 70% 34%, respectively, compared that not BSO. Next, examined...
Seizure is among the most severe FDA black box warnings of neurotoxicity reported on drug labels. Gaining a better mechanistic understanding off-targets causative seizure will improve identification potential risks preclinically. In present study, we evaluated an in vitro panel 9 investigational (Cav2.1, Cav3.2, GlyRA1, AMPA, HCN1, Kv1.1, Kv7.2/7.3, NaV1.1, Nav1.2) and 2 standard (GABA-A, NMDA) ion channel targets with strong correlative links to seizure, using automated electrophysiology....
A prostaglandin derivative, (5Z,9 alpha,11 alpha,13E)-9,11-dihydroxyprosta- 5,13-dienoic acid sodium salt (S-1033), that lowers intraocular pressure with little adverse effect, may have clinical value in the treatment of glaucoma. After [14C]S-1033 (0.2% solution) was instilled into eye a white rabbit, radioactivity and S-1033 appeared systemic plasma so rapidly (tmax, 5 min) eliminated very half-lives 2.8 11.0 min at alpha- beta-phases, respectively. The metabolite, M-1, [1R-[1 alpha,2...