A5017220522- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Cytokine Signaling Pathways and Interactions
- Redox biology and oxidative stress
- Nitric Oxide and Endothelin Effects
- Fibroblast Growth Factor Research
- Cancer Mechanisms and Therapy
- Quinazolinone synthesis and applications
- Synthesis and Catalytic Reactions
- Cancer, Hypoxia, and Metabolism
- Bioactive Compounds and Antitumor Agents
- Enzyme Structure and Function
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Receptor Mechanisms and Signaling
- Protein Kinase Regulation and GTPase Signaling
- Synthesis and Reactivity of Heterocycles
- Psoriasis: Treatment and Pathogenesis
- Electron Spin Resonance Studies
- Estrogen and related hormone effects
- Phosphodiesterase function and regulation
- Synthesis and Biological Evaluation
- Organometallic Compounds Synthesis and Characterization
- Infrared Target Detection Methodologies
- Advanced Computing and Algorithms
Nanospectra Biosciences (United States)
2024
State Street (United States)
2024
Case Western Reserve University
2022
Takeda (United States)
2011-2020
ActiveSite Pharmaceuticals (United States)
2009
New York University
1978
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...
A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation β-adrenergic signaling in vitro studies. Hydrazone derivative 5 1,2,4-triazole 24a were identified as hit compounds by HTS. New scaffold generation SAR studies all parts resulted a 4-methyl-1,2,4-triazole with an N-benzylcarboxamide moiety activity toward selectivity over other kinases. In terms subtype selectivity, these showed enough against GRK1, 5, 6, 7 almost...
583 Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy that accounts for approximately 80-90% of all primary liver cancers and projected to become the third leading cause cancer-related mortality by 2030. Previous work demonstrated human Fibroblast Growth Factor 19 (FGF19) was overexpressed in 20-30% HCC, thereby exerting oncogenic effect via signaling through its cognate receptors FGFR4, FGFR3, co-receptor Klotho b (KLB). Multiple selective covalent FGFR4 inhibitors have...
General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under depletion. We initiated studies aiming at discovery novel GCN2 inhibitors as first-in-class antitumor agents conducted modification substructure sulfonamide derivatives with expected type I half binding on GCN2. Our synthetic strategy mainly corresponding to αC-helix allosteric pocket led significant enhancement potency good...
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides the brain and thereby achieve potentiation nucleotide signaling pathways. This article details expedited optimization our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading discovery clinical candidate 36 (TAK-915), which demonstrates an appropriate...
Trytophan Hydroxylase Type I (TPH1), most abundantly expressed in the gastrointestinal tract, initiates synthesis of serotonin by catalyzing hydroxylation tryptophan presence biopterin and oxygen. We have previously described three series novel, periphery-specific TPH1 inhibitors that selectively deplete tract. now determined co-crystal structures with these at high resolution. Analysis structural data showed each fills binding pocket without reaching into site cofactor pterin, induces major...
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...
In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition slow dissociation kinetics. These medicinal chemistry efforts led to identification compound 3d, which exhibited potent cellular activity, excellent selectivity, antitumor efficacy in COLO205 xenograft mouse model. However, issue formaldehyde adduct formation emerged during...
Activating FGFR3 alterations have been identified in up to 15-20% of muscle-invasive bladder cancer and metastatic urothelial carcinoma (mUC), as high 80% nonmuscle invasive cancers. germline mutations also associated with a variety skeletal dysplasias. Achondroplasia, the most common form dwarfism humans, results from G380R mutation FGFR3. The pan-FGFR inhibitor erdafitinib was approved for treatment mUC but is limited due FGFR isoform off-target toxicities development on-target gatekeeper...
It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation cyclic nucleotide signaling pathways brain regions associated with learning memory. Following our earlier work, this article describes drug design strategy for new series lead compounds structurally distinct from clinical candidate 2 (TAK-915), subsequent medicinal...
Abstract Cortical bone allograft sterilized with a standard γ‐radiation dose of 25–35kGy has demonstrated reduced static and cyclic fracture resistance compared unirradiated bone. To mitigate radiation damage, we recently observed dose‐dependent response high‐cycle fatigue behavior human cortical from 0 to 25 kGy, lower doses exhibiting logarithmically longer lives. The objectives this study were as follows: (1) determine whether toughness, work‐to‐fracture, crack propagation are also...
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...