A5067998074- Cytokine Signaling Pathways and Interactions
- Diet and metabolism studies
- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Pharmacogenetics and Drug Metabolism
- Liver Disease Diagnosis and Treatment
- CAR-T cell therapy research
- Chronic Lymphocytic Leukemia Research
- Cell death mechanisms and regulation
- Cancer Research and Treatments
- Psoriasis: Treatment and Pathogenesis
- Synthesis and biological activity
- Adipose Tissue and Metabolism
- Pancreatic and Hepatic Oncology Research
- Drug Solubulity and Delivery Systems
- Pharmacology and Obesity Treatment
- Pharmaceutical studies and practices
- Pharmacological Effects of Natural Compounds
- Endometriosis Research and Treatment
- Metabolism and Genetic Disorders
- Integrated Circuits and Semiconductor Failure Analysis
- Protein Kinase Regulation and GTPase Signaling
- Lymphoma Diagnosis and Treatment
- Biosimilars and Bioanalytical Methods
- Mast cells and histamine
Reckitt Benckiser (United States)
2024
Bristol-Myers Squibb (United States)
2019-2024
Gilead Sciences (United States)
2024
AbbVie (United States)
2017-2022
University of Minnesota
2013
Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective that traditionally target the catalytically active site this kinase family has been formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting pseudokinase (JH2) domain. Herein we report late stage optimization efforts including structure-guided design and water displacement led BMS-986165 (11) affinity JH2 ligand...
As a member of the Janus (JAK) family nonreceptor tyrosine kinases, TYK2 plays an important role in mediating signaling pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by SPA-based high-throughput screen targeting pseudokinase domain, potently inhibits IL-23 IFNα cellular assays. described work details optimization this poorly selective hit (4) to potent molecules such as 47 48. discoveries herein were critical eventual identification...
A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived ligand as clinical inhibitor currently in late development the treatment of psoriasis, began with survey six-membered heteroaryl groups place N-methyl triazolyl moiety 6. The X-ray co-crystal structure an early lead (12) revealed potential new binding pocket. Exploration pocket resulted two frontrunners candidate. hydrogen bonding interaction Thr599 was achieved tertiary amide moiety,...
It is well established that oxidative and conjugative enzyme activity differs between obese healthy-weight adults. However, the effect of obesity on drug metabolism in children has not been studied extensively. This study examined whether vary with respect to CYP1A2, xanthine oxidase (XO) N-acetyltransferase 2 (NAT2).In vivo XO NAT2 was assessed (n= 9) lean 16) ages 6-10 years using caffeine (118.3 ml Coca Cola®) as probe. Urine samples were collected 2-h increments over 8 h. Caffeine...
1. Venetoclax is a novel, small molecule B-cell lymphoma-2 (BCL-2) inhibitor that has demonstrated clinical efficacy in variety of haematological malignancies. Since venetoclax an P glycoprotein (P-gp) transporter, study was conducted healthy, female volunteers to evaluate the effect on pharmacokinetics digoxin, P-gp probe substrate.2. Volunteers received single oral dose digoxin (0.5 mg) with or without (100 mg). Serial blood samples were obtained for pharmacokinetic assessments and serial...
Elagolix is approved for the management of moderate-to-severe pain associated with endometriosis. The aim this analysis was to develop a physiologically based pharmacokinetic (PBPK) model that describes enzyme-transporter interplay involved in disposition elagolix and predict magnitude drug-drug interaction (DDI) potential as an inhibitor P-glycoprotein (P-gp) inducer cytochrome P450 (CYP) 3A4.A PBPK (SimCYP® version 15.0.86.0) developed using data from vitro, clinical PK DDI studies. Data...
3013 Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 beyond) of each 21-day cycle. Dose escalation (DE) was guided by Bayesian continual reassessment method. In addition to PK...
Antibody drug conjugates (ADCs) provide targeted delivery of cytotoxic agents directly inside tumor cells. However, many ADCs targeting solid tumors have exhibited limited clinical efficacy, in part, due to insufficient penetration within tumors. To better understand the relationship between ADC and previously applied Krogh cylinder models that explore growth dynamics following administration preclinical species were expanded a framework by integrating pharmacokinetics, penetration,...
The pH-dependent solubility of the weakly basic TYK2 inhibitor 1 posed a risk to its advancement, given that drugs with such profiles have exhibited drug–drug interaction (DDI) stomach acid-reducing agents in humans. In rat model pH dependence, preadministration famotidine caused 2.4-fold lower exposure when compared control rats, implying oral absorption can reduce active drug's and translate subtherapeutic treatment. As part mitigation, prodrug strategy was explored by synthesizing...
The aim of this analysis was to use a physiologically based pharmacokinetic (PBPK) model predict the impact changes in dissolution rates on elagolix exposures and define clinically relevant acceptance criteria for dissolution. Varying vitro profiles were utilized PBPK describe absorption formulations used Phase 3 clinical trials be marketed commercial formulations. Single dose studies 200 mg verification under fasted conditions. Additional scenarios evaluated assess exposures. Compared trial...
It is well established that oxidative enzyme activity differs between obese and healthy weight adults. This study examined the interaction age obesity using a rat model of on developmental profiles intrinsic clearance hepatic phase 1 activity. Liver microsomes were isolated from OLETF(obese)/LETO(lean) at various weeks age. CYP 1A2, 2E1, 2D2, xanthine oxidase (XO) was assessed probe substrates. Both effects tested for significance (p‐value ¡Ü0.05). Age related differences observed in all...
<h3>Background</h3> Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis <sup>[1,2]</sup>. binds to unique TYK2 regulatory domain, conferring greater functional selectivity vs JAK inhibitors, which bind catalytic domain. showed superior efficacy placebo phase trial SLE (NCT03252587) <sup>[3]</sup>. <h3>Objectives</h3> This analysis assessed pharmacokinetics (PK),...
<h3>Background</h3> Systemic lupus erythematosus (SLE), a chronic autoimmune disease, is characterized by high clinical and molecular heterogeneity the presence of autoantibodies with various specificities, including those against DNA RNA. While steroids, such as prednisolone, are part standard-of-care for SLE, alternative treatments that overcome steroid resistance minimize risk numerous short- long-term side effects associated their use remain an important unmet need. Toll-like receptors 7...
<h3>Background</h3> Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis.¹ ² binds unique TYK2 regulatory domain, conferring greater functional selectivity vs JAK inhibitors, which bind catalytic domain. showed superior efficacy placebo phase trial SLE (NCT03252587).³ This analysis assessed pharmacokinetics (PK), profile compared to and exposure-response (E-R)...
It is well established that oxidative enzyme activity differs between obese and healthy weight adults. However, the effect of obesity on drug metabolism in children poorly understood. Therefore this study examined whether vary with respect to phase I activity. In vivo CYP 1A2, 3A 2D6 was assessed African‐American ages 6–10yrs by measuring administered dextromethorphan (0.5mg/kg; max=30 mg) caffeine (11.5mg). Cumulative 8hr metabolic urine ratios (MR) dextromethorphan/dextrorphan...