ABSTRACT
The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvß3 and αvß5 significantly change the biological activities against αvß6 and αvß8. This resulted in the discovery of a pan αv antagonist (compound 39, 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).
Subject(s)
Idiopathic Pulmonary Fibrosis/pathology , Integrin alphaV/chemistry , Phenylbutyrates/chemistry , Administration, Oral , Animals , Antigens, Neoplasm/metabolism , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Half-Life , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Integrin alphaV/metabolism , Integrin alphaVbeta3/antagonists & inhibitors , Integrin alphaVbeta3/metabolism , Integrins/antagonists & inhibitors , Integrins/metabolism , Molecular Conformation , Molecular Docking Simulation , Phenylbutyrates/pharmacokinetics , Phenylbutyrates/therapeutic use , Protein Structure, Tertiary , Rats , Receptors, Vitronectin/antagonists & inhibitors , Receptors, Vitronectin/metabolism , Structure-Activity RelationshipABSTRACT
High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
Subject(s)
Receptors, Gastrointestinal Hormone/agonists , Receptors, Gastrointestinal Hormone/chemistry , Receptors, Neuropeptide/agonists , Receptors, Neuropeptide/chemistry , Animals , Binding Sites , Cell Membrane/metabolism , Chemistry, Pharmaceutical/methods , Combinatorial Chemistry Techniques , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Chemical , Molecular Structure , Receptors, G-Protein-Coupled/metabolism , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Changes in environmental legislation and standards governing healthcare waste, such as the Hazardous Waste Regulations are expected to have a significant impact on healthcare waste quantities and costs in England and Wales. This paper presents findings from two award winning case study organizations, the Cardiff and Vale NHS Trust and the Cornwall NHS Trust on 'systems' they have employed for minimizing waste. The results suggest the need for the development and implementation of a holistic range of systems in order to develop best practice, including waste minimization strategies, key performance indicators, and staff training and awareness. The implications for the sharing of best practice from the two case studies are also discussed.