Drug Discovery: From Hits to Clinical Candidates

The H₃ drug discovery process has been constantly refined from the original idea to the proof-of-concept in human. Along with the preclinical development of potent drug candidates, the need for radiolabeled H₃ ligands has been crucial to study the histamine H₃-ligand interactions and therefore to run appropriate in vitro binding and functional screening assays. The exponential patent application filings and public disclosures of widely diverse chemical series demonstrated the ability of medicinal chemists to identify key features for high-affinity ligands and transformed their creativity into innovative compounds. Such work has been gratefully supported by computer-aided drug design activities. Chemically diverse hits were found, as exemplified by compound 147, 148, and 149, displaying weak to moderate antagonism properties. In contrast to the classical concept “one disease—one target—one drug,” the multiple targeting approaches by a single chemical entity or a combination of compounds are often realized with marketed drugs for complex diseases.