A novel class of H3 antagonists derived from the natural product guided synthesis of unnatural analogs of the marine bromopyrrole alkaloid dispyrin

This Letter describes the natural product guided synthesis of unnatural analogs of the marine bromopyrrole alkaloid dispyrin, and the resulting SAR of H3 antagonism. Multiple rounds of iterative parallel synthesis improved human H3 IC50 ∼33-fold, and afforded a new class of H3 antagonists based on the novel bromotyramine core of dispyrin.

Graphical abstractThe natural product guided synthesis of analogs of the marine alkaloid dispyrin, and the resulting SAR of H3 antagonism, is described. Three rounds of iterative parallel synthesis generated 24d, a potent H3 antagonist (IC50 = 30 nM, Ki = 70 nM) with a novel chemotype based on the bromotyramine motif of dispyrin.Figure optionsDownload full-size imageDownload as PowerPoint slide