A5070822235- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Pharmacological Effects and Toxicity Studies
- Gastroesophageal reflux and treatments
- Epilepsy research and treatment
- Cancer therapeutics and mechanisms
- Crystallization and Solubility Studies
- Sulfur Compounds in Biology
- Trace Elements in Health
- Biochemical and Molecular Research
- Analytical Chemistry and Chromatography
- Protein Tyrosine Phosphatases
- Neuroscience and Neuropharmacology Research
- Metabolomics and Mass Spectrometry Studies
- Video Surveillance and Tracking Methods
- Antibiotic Resistance in Bacteria
- Chronic Lymphocytic Leukemia Research
- DNA Repair Mechanisms
- X-ray Diffraction in Crystallography
- Advanced Neural Network Applications
- Brain Tumor Detection and Classification
- Antibiotics Pharmacokinetics and Efficacy
Biogen (United States)
2019-2023
Maulana Azad National Institute of Technology
2022
Absorption, distribution, metabolism, and excretion (ADME), which collectively define the concentration profile of a drug at site action, are critical importance to success candidate. Recent advances in machine learning algorithms availability larger proprietary as well public ADME data sets have generated renewed interest within academic pharmaceutical science communities predicting pharmacokinetic physicochemical endpoints early discovery. In this study, we collected 120 internal...
Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In early stage MS, inflammation primary driver disease progression. There remains an unmet need develop high efficacy therapies with superior safety profiles prevent processes Herein, we describe discovery BIIB091, structurally distinct orthosteric ATP competitive, reversible inhibitor...
Herein we describe the design, synthesis, and evaluation of a novel series oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement critical consideration conformational restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties desirable ADME/PK profile. This compound demonstrated robust Aβ42 reductions subsequent Aβ37 increases both rodent brain CSF at 30 mg/kg dosed orally.
Familial Alzheimer's disease (FAD) is caused by mutations in the amyloid precursor protein (APP) or presenilin (PS). Most PS mutations, which account for majority of FAD cases, lead to an increased ratio longer shorter forms beta (Aβ) peptide. The therapeutic rationale γ-secretase modulators (GSMs) based on this genetic evidence as well enzyme kinetics measurements showing changes processivity complex. This analysis suggests that GSMs could potentially offset some effects APP processing,...
Abstract Transporters can play a key role in the absorption, distribution, metabolism, and excretion of drugs. Understanding these contributions early drug discovery allows for more accurate projection clinical pharmacokinetics. One method to assess impact transporters vivo involves co‐dosing specific inhibitors. The objective present study was optimize dose route administration P‐glycoprotein (P‐gp) inhibitor, valspodar (PSC833), dual P‐gp/breast cancer resistance protein (BCRP) elacridar...
The recent approval of aducanumab for Alzheimer's disease has heightened the interest in therapies targeting amyloid hypothesis. Our research focused on identification novel compounds to improve processing by modulating gamma secretase activity, thereby addressing a significant biological deficit known plague familial form disease. Herein, we describe design, synthesis, and optimization new modulators (GSMs) based previously reported oxadiazine 1. Potency improvements with focus predicted...
Three quinuclidine derivatives (FRM-1, FRM-2 and FRM-3) were subject to significant mass loss cellular retention in Caco-2 permeation experiments. The apparent permeability coefficient (Papp) calculated with either 'sink' (Papp,sink) or 'non-sink' (Papp,nonsink) method was significantly biased. As a result, simplified 3-compartmental distribution model applied this study derive the 'intrinsic' Papp (Papp,int) understand impact of on estimating active efflux ratio (ER) values.Time-courses...