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• Structure

  Atogepant (MK-8031/AGN-241689) is a polycyclic molecule containing four chiral centers and three aromatic and aliphatic rings. An intriguing feature is the 2-azaspiro [4.4]nonan-1-one (spiroazaindane) motif in an S configuration, also present in earlier preclinical leads from Merck. The azospiro bispyridine unit is linked via an amide bond to a piperidine-2-one ring; the amide linkage is reversed to that seen in earlier leads to avoid the potential release of a toxic aniline. The piperidine-2-one ring is heavily functionalized with 6-(R)-methyl, 5-(R)-2,3,6-trifluorophenyl substituents. The 2,3,6 pattern of fluoro substituents provided a ~fourfold increase in atogepant affinity compared with ubrogepant, which contains an unsubstituted phenyl ring. The fluorine substitution pattern in atogepant may be responsible for alleviating the hepatotoxicity associated with some other gepants, such as telcagepant. Notably, the piperidinone is masked with a 2,2,2,-trifluoroethyl group, a substitution that provided improved telcagepant's potency, bioavailability, and half-life. Atogepant’s molecular weight (603 g/mol), the presence of five H-bond acceptors and two H-bond donors, and its large polar surface area (109.29 Å2) may limit penetration via passive diffusion through the blood-brain barrier. ;

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