The pyridazine heterocycle in molecular recognition and drug discovery.

ABSTRACT

The pyridazine ring is endowed with unique physicochemical properties, characterized by weak basicity, a high dipole moment that subtends π-π stacking interactions and robust, dual hydrogen-bonding capacity that can be of importance in drug-target interactions. These properties contribute to unique applications in molecular recognition while the inherent polarity, low cytochrome P450 inhibitory effects and potential to reduce interaction of a molecule with the cardiac hERG potassium channel add additional value in drug discovery and development. The recent approvals of the gonadotropin-releasing hormone receptor antagonist relugolix (24) and the allosteric tyrosine kinase 2 inhibitor deucravacitinib (25) represent the first examples of FDA-approved drugs that incorporate a pyridazine ring. In this review, the properties of the pyridazine ring are summarized in comparison to the other azines and its potential in drug discovery is illustrated through vignettes that explore applications that take advantage of the inherent physicochemical properties as an approach to solving challenges associated with candidate optimization.