A5035560905- Antibiotics Pharmacokinetics and Efficacy
- Cancer Mechanisms and Therapy
- Antibiotic Resistance in Bacteria
- Quinazolinone synthesis and applications
- Liver physiology and pathology
- Enzyme function and inhibition
- Drug Transport and Resistance Mechanisms
- Pneumonia and Respiratory Infections
- Ethics and Social Impacts of AI
- Pancreatic and Hepatic Oncology Research
- Pharmacogenetics and Drug Metabolism
- Commutative Algebra and Its Applications
- Rings, Modules, and Algebras
- Antimicrobial Resistance in Staphylococcus
- Phenothiazines and Benzothiazines Synthesis and Activities
- Advanced Graph Neural Networks
- PI3K/AKT/mTOR signaling in cancer
- Pharmacological Effects and Toxicity Studies
- Cognitive Functions and Memory
- Explainable Artificial Intelligence (XAI)
- Antifungal resistance and susceptibility
- Tuberculosis Research and Epidemiology
- Ion channel regulation and function
- Acute Kidney Injury Research
- Pharmaceutical studies and practices
Innoviva (United States)
2024-2025
Harvard University Press
2024
Amgen (United States)
2008-2023
Entasis Therapeutics (United States)
2017-2023
Harvard University
2023
AstraZeneca (United States)
2015-2017
Innovative Medicines Initiative
2015
Tumorigenesis is a multistep process in which oncogenes play key role tumor formation, growth, and maintenance. MET was discovered as an oncogene that activated by its ligand, hepatocyte growth factor. Deregulated signaling the c-Met pathway has been observed multiple types. Herein we report discovery of potent selective triazolopyridazine small molecules inhibit activity.
The objective of this study was to investigate the risk attenuated efficacy due adaptive resistance for siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined cation-adjusted Mueller-Hinton broth (MHB) and Chelex-treated, dialyzed MHB (CDMHB). Spontaneous assessed at 2× 16× MIC resulting mutants sequenced. Efficacy evaluated neutropenic mouse thigh model 3.13 400 mg/kg body weight every 3 h 24...
Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward β-lactam antibiotics. The hydrolytic enzymes called β-lactamases responsible for a large proportion of the phenotype. β-Lactamase inhibitors (BLIs) can be administered in combination with antibiotics negate action β-lactamases, thereby restoring activity β-lactam. Newly developed BLIs offer some advantage over older terms enzymatic spectrum but limited...
Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition over VEGFR2. However, studies revealed generation active, nonselective metabolites. Blocking this metabolic hot spot led to discovery 17 (AMG 458). When dosed orally, significantly inhibited tumor growth NIH3T3/TPR-Met and U-87 MG xenograft models no adverse effect on body weight.
ETX2514 is a non-β-lactam serine β-lactamase inhibitor in clinical development that has greater potency and broader spectrum of inhibition than the related diazabicyclooctanone avibactam. Despite opening its cyclic urea ring upon acylation, avibactam can recyclize dissociate intact from certain β-lactamases. We investigated reversibility acylation 10 β-lactamases representing Ambler classes A, C, D. Dissociation rate constants varied widely between enzymes were lowest for class For most...
Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure–activity relationships for novel series 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate vivo testing rats. The binding site 52 on was determined to be distinct from local...
ABSTRACT Infections caused by Acinetobacter baumannii are increasingly multidrug resistant and associated with high rates of morbidity mortality. Sulbactam is a β-lactamase inhibitor intrinsic antibacterial activity against A. . Durlobactam non-β-lactam an extended spectrum compared to other inhibitors its class. In vitro pharmacodynamic infection models were undertaken establish the pharmacokinetic/pharmacodynamic (PK/PD) index magnitudes sulbactam durlobactam efficacy simulate epithelial...
Abstract Recepteur d'origine nantais (RON) is a receptor tyrosine kinase closely related to c-Met. Both receptors are involved in cell proliferation, migration, and invasion, there evidence that both deregulated cancer. Receptor overexpression has been most frequently described, but other mechanisms can lead the oncogenic activation of RON They include activating mutations or gene amplification for c-Met constitutively active splicing variants RON. We identified novel inhibitor c-Met,...
In vitro intrinsic metabolic clearance (CL<sub>int</sub>) is used routinely for compound selection in drug discovery; however, CL<sub>int</sub> often underpredicts vivo (CL). Forty-one proprietary compounds and 16 marketed drugs were selected to determine whether permeability efflux status could influence the predictability of CL from obtained liver microsomal hepatocyte incubations. For many examined, rat was significantly underpredicted using well stirred model incorporating both fraction...
To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class monocyclic β-lactams are stable to metallo-β-lactamases and have excellent P. aeruginosa activities due their ability exploit iron uptake machinery Gram-negative bacteria. Our medicinal chemistry plan identifying a molecule with optimal potency physical properties activity in vivo efficacy. Modifications monocarbam linker, siderophore, oxime...
The current CLSI and EUCAST clinical susceptible breakpoint for 600 mg q12h dosing of ceftaroline (active metabolite fosamil) Staphylococcus aureus is ≤1 mg/L. Efficacy data S. infections with MIC ≥2 mg/L are limited. This study was designed to generate in-depth pharmacokinetic/pharmacodynamics (PK/PD) understanding isolates inhibited by ≥ 2 using an in vitro hollow-fibre infection model (HFIM). PK/PD target investigated against 12 diverse characterized MRSA MICs or 4 q8h 24 h. These carried...
Increasingly resistant Enterobacteriaceae have emerged as a health threat in both hospital and community settings. Infections of the urinary tract, once often treated with oral agents community, are requiring increased hospitalization use intravenously administered for effective treatment. These isolates carry extended spectrum β-lactamases (ESBLs) carbapenemases that necessitate need an inhibitor to cover broad range β-lactamases. ETX1317 is novel diazabicyclooctane class serine β-lactamase...
Multi-drug resistant (MDR)
Graph Neural Networks (GNNs) have become increasingly important due to their representational power and state-of-the-art predictive performance on many fundamental learning tasks. Despite this success, GNNs suffer from fairness issues that arise as a result of the underlying graph data aggregation mechanism lies at heart large class GNN models. In article, we examine categorize techniques for improving GNNs. We these by whether they focus in pre-processing, in-processing (during training),...
We previously reported that the accuracy of clearance (CL) prediction could be differentiated by permeability. CL was drastically under-predicted in vitro metabolic intrinsic (CL(int)) for compounds with low permeability (<5 × 10(-6) cm/s). determined apparent uptake CL(int) measuring initial disappearance from medium using attached rat hepatocytes and parent depletion suspended (cells medium). Uptake were comparable highly permeable marker compounds. In contrast, 3- to 40-fold higher than...
1. Negamycin exerts its antimicrobial activity by inhibiting bacterial protein synthesis and is efficacious in animal models of infection. In order to optimize negamycin exposure for therapeutic purposes, pharmacokinetics pre-clinical species were determined. 2. has a dipeptide-like structure with logD7.4 < -1, causing low permeation into Caco-2 cells, low-oral bioavailability rats 6% low-plasma binding 10% mouse, rat, dog human plasma. degradation rates microsomes hepatocytes predicted...
Sulbactam-durlobactam is approved for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates Acinetobacter baumannii-calcoaceticus complex. Patients with serious infections may require support continuous renal replacement therapy (CRRT), which presents challenges optimal dosing antibiotics. regimens were derived this population using an ex vivo CRRT model Monte Carlo simulation (MCS). Transmembrane clearance (CLTM) was determined in...
Abstract Background Optimal dosing of antibiotics in patients on CRRT is complicated by factors that can influence drug adsorption and clearance including filter type, mode, effluent rate (ER), the drug’s properties itself. SUL-DUR a novel combination antibiotic under development for management Acinetobacter baumannii infections. We sought to characterize SUL DUR transmembrane (CLTM) an ex vivo model. Methods CLTM was determined hemofiltration (CVVH) hemodialysis (CVVHD) modes using...
Learning fair graph representations for downstream applications is becoming increasingly important, but existing work has mostly focused on improving fairness at the global level by either modifying structure or objective function without taking into account local neighborhood of a node. In this work, we formally introduce notion and develop computational framework learning such locally embeddings. We argue that more appropriate since GNN-based models operate Our two main components are...