Pfizer Global Research and Development Groton Laboratories, CT 06340, USA.
Published: June 2005
AI Article Synopsis
Article Abstract
A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
Pulmonary fibrosis (PF) is a progressive, fatal lung disease lacking effective treatments. Autotaxin (ATX) plays a crucial role in exacerbating inflammation and fibrosis, making it a promising target for fibrosis therapies. Herein, starting from PAT-409 (Cudetaxestat), a series of novel ATX inhibitors bearing 1-indole-3-carboxamide, 4,5,6,7-tetrahydro-7-pyrazolo[3,4-]pyridin-7-one, or 4,5,6,7-tetrahydro-1-pyrazolo[4,3-]pyridine cores were designed based on the structure of ATX hydrophobic tunnel.
Antimicrobial resistance is a significant cause of mortality globally due to infections, a trend that is expected to continue to rise. As existing treatments fail and new drug discovery slows, the urgency to develop novel antimicrobial therapeutics grows stronger. One promising strategy involves targeting bacterial systems exclusive to pathogens, such as the transcription regulator protein GabR.
Co-use of xylazine with opioids is a major health threat in the United States. However, a critical knowledge gap exists in the understanding of xylazine-induced pharmacological and pathological impact. Xylazine is mostly known as an agonist of α2-adrenergic receptors (α2-ARs), but its deleterious effects on humans cannot be fully reversed by the α2-AR antagonists, suggesting the possibility that xylazine targets receptors other than α2-ARs.
Unlocking the power of personalised medicine in oncology hinges on the integration of clinical trial data with translational data (i.e. biospecimen-derived molecular information).
Background: Asthma is a global chronic respiratory disease with complex pathogenesis. While current therapies offer some relief, they often fall short in effectively managing symptoms and preventing exacerbations for numerous patients. Thus, understanding its mechanisms and discovering new drug targets remains a pressing need for better treatment.
