Publications by authors named "A S Kalgutkar"
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies.
View Article and Find Full Text PDFVaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PL) is one of the two essential cysteine proteases involved in viral replication.
View Article and Find Full Text PDFThe purpose of this work was to determine the feasibility of supporting a clinical microdose study for PF-06882961 (danuglipron), an oral small molecule agonist of the GLP-1 receptor, by LC-MS/MS. Statistical instrument parameter optimization using response surface methodology was employed to develop a LC-MS/MS method for the analyte, PF-06882961. An LC-MS/MS method was developed and validated to support a proof of concept microdose pharmacokinetics preclinical study in monkeys, administered PF-06882961 (0.
View Article and Find Full Text PDFArticle Synopsis
- Understanding the carcinogenic potential of nitrosamines is crucial for setting safe consumption limits, as these substances are found in various products like food, water, and tobacco.
- Recent findings of nitrosamines in pharmaceuticals underscore the necessity for reliable methods to establish these limits.
- The text discusses two computational models that use quantum mechanical properties and existing data to evaluate the carcinogenic potency of nitrosamines, which can help assess untested nitrosamines for safe intake levels.
Article Synopsis
- - This annual review is the eighth installment in a series that began in 2016, focusing on significant articles in biotransformation research.
- - The review aims to explore and share influential findings that contribute to the field.
- - Each article is summarized with key points, followed by commentary, relevant figures, and references to enhance understanding.