PHARMACOKINETICS OF STILBENE ANALOGUES AND THEIR APPLICATION AS NOVEL ANTI-INFLAMMATORY AGENTS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Abstract

Chronic obstructive pulmonary disease (COPD) is an escalating global health problem associated with massive healthcare costs. There are currently no effective therapies which can significantly ameliorate the underlying inflammation and alter the natural history of this disease. Resveratrol, the stilbene analogue found naturally in berries, has anti-oxidant and anti-inflammatory effects in several disease models related to airway inflammation. However, its therapeutic application is limited by its relatively weak potency and poor pharmacokinetics and its anti-inflammatory mechanisms have not been fully elucidated. This project extensively investigated the pharmacology of stilbene analogues by first profiling the pharmacokinetics of some analogues to identify possible structural determinants of pharmacokinetics, followed by examining the anti-inflammatory effects and cellular mechanisms of these compounds to identify promising drug candidates. These studies established isorhapontigenin as the most potent stilbene analogue with better pharmacokinetics than resveratrol which substantiate its further development as a novel anti-inflammatory agent for COPD.