A5001793302- Hormonal Regulation and Hypertension
- X-ray Diffraction in Crystallography
- Estrogen and related hormone effects
- Crystallization and Solubility Studies
- Pharmacogenetics and Drug Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Peptidase Inhibition and Analysis
- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Biochemical and Molecular Research
- Chronic Lymphocytic Leukemia Research
- Chemical Synthesis and Analysis
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Coenzyme Q10 studies and effects
- Advanced Breast Cancer Therapies
- Computational Drug Discovery Methods
- Ferrocene Chemistry and Applications
- Molecular spectroscopy and chirality
- Lymphoma Diagnosis and Treatment
- Protein Degradation and Inhibitors
- Respiratory and Cough-Related Research
- Neuropeptides and Animal Physiology
- Protease and Inhibitor Mechanisms
- Aldose Reductase and Taurine
- Click Chemistry and Applications
Amgen (United States)
2007-2018
Array BioPharma (United States)
2007
Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design synthesis of a boronic acid modified fulvestrant (5, ZB716), which binds to ERα competitively (IC50 = 4.1 nM) effectively downregulates in both tamoxifen-sensitive tamoxifen-resistant cancer cells. Furthermore, It has superior oral bioavailability (AUC 2547.1 ng·h/mL) mice,...
Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in subpopulation of sensory neurons peripheral nervous system, including nerve circuitry implicated migraine pathogenesis: trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an between TRPM8 reduced risk migraine. This disclosure focuses on medicinal-chemistry efforts to improve druglike properties initial...
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests selective inhibition 11β-HSD1 could potentially treat metabolic syndrome as well 2 diabetes. Through modification our initial lead 1, we have discovered trifluoromethyl thiazolone 17. This compound had a Ki 22 nM, possessed low in vivo clearance, and showed 91% adipose enzymatic activity mouse ex pharmacodynamic model.
A 2-aminothiazole derivative 1 was developed as a potential inhibitor of the oncology target AKT, serine/threonine kinase. When incubated in rat and human liver microsomes presence NADPH, underwent significant metabolic activation on its ring, leading to substantial covalent protein binding. Upon addition glutathione, binding reduced significantly, multiple glutathione adducts were detected. Novel metabolites from vitro incubates characterized by LC-MS NMR discern mechanism bioactivation. An...
A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). One our lead from this activated human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate PXR activity, we prepared analogues that contained polar groups on right-hand side thiazolone. Several amides or alcohols appended C-5 position thiazolone showed a significant reduction in activity. Through these...
The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this have been studied as promising candidates for treatment chronic pain. We identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists the human receptor. Our previously communicated lead, compound 2, served proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance metabolic profiling, we performed structure−activity...
All eight of the major active metabolites (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221, compound 1), an inhibitor 11β-hydroxysteroid dehydrogenase type 1 that has entered clinic for treatment 2 diabetes, were synthetically prepared and confirmed by comparison with samples generated in liver microsomes. After further profiling, we determined metabolite was equipotent to on human 11β-HSD1 had lower vivo clearance higher bioavailability rat...
e15062 Background: The first generation irreversible BTK inhibitor ibrutinib has been approved for the treatment of B cell-related diseases, including chronic lymphocytic leukemia (CLL), several years. However, CLL patients who used may develop drug resistance due to acquired mutations, in particular C481S that directly impacts binding ibrutinib. In recent years, efforts have made second reversible inhibitors are effective against both wild-type and mutated B-cell malignancies. LOXO-305...
e15068 Background: It has been an on-demand task to develop a BTK inhibitor of significant brain exposure, critical property for extending its usages treat Primary Central Nervous System Lymphoma (PCNSL) and autoimmune disorders. PCNSL is aggressive extra nodal non-Hodgkin lymphoma that exclusively invades the central nervous system (CNS). Tirabrutinib, irreversible with limited first approved treatment recurrent or refractory primary recently. PRN2246 another claimed be currently in...