Vanin-1 is a glycosylphosphatidylinositol-anchored, cell surface associated pantetheinase that catalyzes the hydrolysis of pantetheine to pantothenic acid (vitamin B5) and cysteamine. Vanin-1 has been implicated in inflammatory diseases with a large oxidative stress component including inflammatory bowel disease (IBD). Support for the role vanin-1 in this disease includes over-expression in patients with the main forms of IBD, ulcerative colitis and Crohn’s disease. In addition, protection of vanin-1 deficient mice against experimental colitis has been reported. Thus, inhibition of vanin-1 represents a novel approach for the treatment of IBD, as well as other inflammatory conditions.<br/>An HTS was run to identify vanin-1 inhibitors leading to the discovery of a series of aminopyrimidines containing a diaryl ketone linker that remained as the mainstay of the early medicinal chemistry efforts. Concerns with our ability to advance a compound from this series as a candidate for human clinical trials due to its human pharmacokinetic prediction and potential complications during development caused by the presence of the diaryl ketone moiety led us to look for ketone replacements. This presentation will describe the successful replacement of the ketone moiety with an amide leading to the discovery of a series of pyrimidine carboxamides. The rapid optimization of this series to deliver (2-((pyrazin-2-ylmethyl)amino)pyrimidin-5-yl)(8-oxa-2-azaspiro[4.5]decan-2-yl)methanone as a potent, selective, and orally bioavailable vanin-1 inhibitor suitable for progression as a preclinical candidate for the treatment of inflammatory conditions will be presented.

Discovery of a series of pyrimidine carboxamides as inhibitors of vanin-1 for the treatment of inflammatory conditions

2019 Fall National Meeting

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