ABSTRACT
The G protein-coupled P2Y2 receptor, activated by ATP and UTP has been reported as a potential drug target for a wide range of important clinical conditions, such as tumor metastasis, kidney disorders, and in the treatment of inflammatory conditions. However, pharmacological studies on this receptor have been impeded by the limited reported availability of stable, potent and selective P2Y2R antagonists. This article describes the design and synthesis of AR-C118925, a potent and selective non-nucleotide antagonist of the P2Y2 receptor discovered using the endogenous P2Y2R agonist UTP as the chemical starting point.
Subject(s)
Dibenzocycloheptenes/chemical synthesis , Purinergic P2Y Receptor Antagonists/chemical synthesis , Pyrimidinones/chemical synthesis , Receptors, Purinergic P2Y2/metabolism , Uridine Triphosphate/chemistry , Dibenzocycloheptenes/chemistry , Dibenzocycloheptenes/metabolism , Drug Evaluation, Preclinical , Humans , Protein Binding , Purinergic P2Y Receptor Antagonists/chemistry , Purinergic P2Y Receptor Antagonists/metabolism , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Receptors, Purinergic P2Y2/chemistry , Uridine Triphosphate/metabolismABSTRACT
Chronic obstructive pulmonary disease (COPD) is characterized by long periods of stable symptoms, but exacerbations occur, which result in a permanent worsening of symptoms. Previous studies have shown a link between bacterial colonization of the lower airways of COPD sufferers and an increase in exacerbation frequency. One of the most frequent bacterial colonizers is Streptococcus pneumoniae. To mimic this aspect of COPD, a murine model of low-level pneumococcal colonization in the lung has been developed, in which S. pneumoniae persisted in the lungs for at least 28 days. From day 14 postinfection, bacterial numbers remained constant until at least 28 days postinfection, and animals showed no outward signs of disease. The bacterial presence correlated with a low-level inflammatory response that was localized to small foci across the left and inferior lobes of the lung. The cellular response was predominantly monocytic, and focal fibroplasia was observed at the airway transitional zones. Physiological changes in the lungs were investigated with a Forced Maneuvers system. This new model provides a means of study of a long-term pulmonary infection with a human pathogen in a rodent system. This is an excellent tool for the development of future models that mimic complex respiratory diseases such as COPD and asthma.