Hematopoietic prostaglandin D synthase (HPGDS) is primarily expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts prostaglandin D2 (PGD2) from prostaglandin H2, the common substrate of numerous prostanoid enzymes. PGD2 is a mediator thought to play a pivotal role in airway allergy and inflammatory processes. The lead generation phase of this program identified several lead series that inhibited H-PGDS activity. These lead series had very broad structural diversity. In this talk we will describe the biophysical characterization utilizing ITC, SAR and cocrystal structures that allowed identification of critical interaction to a conserved water molecule. This water mediated hydrogen bond changed the thermodynamic signature of a lead series from being entropic to enthalpic. The thermodynamic signature of an enthalpic lead series translated into series that illustrated specific SAR in our enzyme functional assay. This critical understanding of binding requirement allowed the optimization of a pyridine lead series resulting in an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.

Thermodynamic signature of various lead series for hematopoietic prostaglandin D synthase

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.