1980 Award in Medicinal Chemistry: Medicinal chemistry and dynamic structure-activity analysis in the discovery of drugs acting at histamine H2 receptors.

Applications of physical organic chemistry and dynamic structure--activity analysis are illustrated by studies made during the development of specific drugs acting as antagonists of histamine at H2 receptors. Imidazolylalkylguanidines, isothioureas, and carboxamidines were found to be partial agonists, and attempts were made to remove the agonist component by lengthening the side chain and replacing the strongly basic group in these molecules by nonbasic groups. This approach furnished thioureas and cyanoguanidines as competitive antagonist, e.g., burimamide and cimetidine. Thoughts about molecular interactions led to the discovery of other nonbasic chemical groups for antagonist structures, in particular 1,1-diamino-2-nitroethenes and 2-amino-pyrimidine-4-ones (isocytosines). Such moieties are incorporated, respectively, in the recently described antagonist drugs ranitidine and oxmetidine.