Myeloperoxidase (MPO), a heme-containing peroxidase, releases hypochlorous acid as an important component of the body’s defense against invading microbes. However, high plasma MPO levels and MPO-specific oxidation products have been associated with chronic inflammatory diseases including atherosclerosis, so inhibitors of MPO have been proposed to provide therapeutic potential. The crystal structure overlay of two potent MPO inhibitors inspired the design and synthesis of macrocyclic MPO inhibitors. The macrocycles were designed with the goal to improve potency and physical properties. A variety of macrocyclization synthesis strategies were evaluated for rapid SAR study, including ring-closing Mitsunobu, Ullmann, and palladium-catalyzed cross-coupling reactions. An intramolecular Suzuki-Miyaura reaction provided the best general access to several macrocycles with varying ring size and structural complexity, resulting in MPO inhibitors with nanomolar potency.

Macrocyclic triazolopyridines as potent inhibitors of myeloperoxidase

254th National Meeting (2017)

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