Histamine receptors modulate a broad range of physiological processes. From this class of receptors, antagonists of the H1 and H2 receptors have been developed into clinically used drugs and demonstrate the high druggability of the target class. The most recent addition of this family is the H4 receptor, which is recognized for its role in inflammation. In early efforts we optimized simple diaminopyrimidine structures, which were prone to fast metabolism, poor PK properties, and often demonstrated H4 agonism in a rodent functional assay. Through modulation of different elements of the chemotype, we improved H4 selectivity, drug-like properties, and in vivo activity. We explored multiple ring fusions forming conformationally restrained analogs and delivered potent, consistent in vitro H4 antagonism leading to efficacy in rodent models of inflammation and pain.DisclosuresBDW is an AbbVie employee.This study was sponsored by AbbVie. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the publication.

Discovery of rigidified diaminopyrimidines as histamine H<sub>4 </sub>receptor antagonists and their profiles in preclinical models of pain

246th National Meeting (2013)

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Discovery of rigidified diaminopyrimidines as histamine H4 receptor antagonists and their profiles in preclinical models of pain

Discovery of rigidified diaminopyrimidines as histamine H₄receptor antagonists and their profiles in preclinical models of pain