SAR studies toward discovery of emvododstat (PTC299), a potent dihydroorotate dehydrogenase (DHODH) inhibitor

Dihydroorotate dehydrogenase (DHODH) is the enzyme that catalyzes a rate-determining step during the de novo synthesis of uridine, an important source of cellular pyrimidine nucleotides. Ability to modulate the activity of this enzyme may be used to control diseases associated with rapid, out-of-control cell growth in oncology, immunology, and virology. Emvododstat (PTC299) is a tetrahydro-β-carboline DHODH inhibitor discovered through the GEMS technology (Gene Expression Modulation by Small-Molecules). Described in this paper is the lead optimization campaign that culminated in the discovery of this highly potent DHODH inhibitor. [Display omitted] •A series of dihydroorotate dehydrogenase inhibitors with a novel tetrahydro-β-carboline scaffold discovered and optimized.•C (6)-carboline substituent, free NH on the indole, and (S)-configuration of the C (1)-center are crucial for activity.•Other structural elements important for activity and pharmaceutical properties are described.•The top compound has activity in a tumor xenograft and no identified toxicity issues.•Good oral exposure can be achieved despite poor aqueous solubility.