molecules of the month

“compound 3”

vanin-1 pantetheinase inhibitor

preclinical candidate for IBD

from HTS + SBDD

Journal of Medicinal Chemistry

Pfizer, Cambridge, MA + Groton, CT

Chemical structure of molecule compound 3 Vanin-1
2 mins read

Vanin-1 is a biotinidase (nitrilase superfamily) that hydrolyzes pantetheine. Despite the critical role of pantetheine, vanin-1 deficient mice don’t appear to have issues, but may be protected in inflammatory disease settings like IBD. Since human vanin-1 coverage requirements are unknown, the Pfizer vanin-1 program took a “no-regrets” approach to target dose and dose prediction, and deprioritized a ketone-containing lead with high projected human dose (850 mg BID). The ketone was replaced with an amide and optimized to “compound 3.” The article is an excellent case study for drug discovery on a novel target, with rigorous characterization of properties along the way. For example, vanin-1 is proteolytic, so the hypothesis that the new amide series may be a substrate for vanin-1…

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