Identification of alkylidene hydrazides as glucagon receptor antagonists

High throughput screening of our small molecule combinatorial library ident ified a class of benzoylnaphthalenehydrazones with modest affinity for the human glucagon receptor. Optimization of this initial hit through a series of targeted libraries and traditional medicinal chemistry led to ligands wi th nanomolar affinities. Pharmacological evaluation demonstrated that these ligands were competitive glucagon receptor antagonists. Intravenous admini stration of a representative benzoylnaphthalenehydrazone into rats attenuat ed glucagon-stimulated glucose levels.