The long-term objective of this proposal is to identify and develop new drugs by identifying novel ligands for G protein-coupled receptors (GPCRs). GPCRs have been shown to be the molecular target of many marketed drugs. Several macrolide structures have been shown to act as agonists or antagonists against GPCRs, so a combinatorial library of macrolide structures screened against a battery of orphan GPCRs would likely yield an array of agonists and antagonists. These macrolide ligands could then be used to elucidate the biology of the orphan receptors, and would likely lead to the development and commercialization of new drugs. This proposal is thus directed towards the synthesis of a library of macrolides using high-speed parallel synthesis. During Phase I, the chemistry to produce the first two subsets of compounds will be developed, and analogs generated will be screened for activity against the motilin receptor as a proof-of-concept. Phase II will be directed to development of the remaining chemistry and the synthesis of the remaining library members. The library will be expanded to ca. 1000 members, and will be screened in collaboration with Glaxo SmithKline.
Agonists of the Motilin receptor could be used in the attachment of gastroesophageal reflux disease and gastroparesis. Both diseases have significant markets, and development of suitable treatments would have substantial commercial prospects. The discovery of agonist or antagonist ligands for orphan GPCRs would aid in the characterization of novel targets for new drugs.
