molecules of the month

The FORUM Pharmaceuticals CNS-penetrant gamma secretase inhibitor and preclinical candidate, FRM-024, is an advanced example of the use of an oxadiazine as an amide isostere. While amide isosteres are frequently proposed, it is often difficult to implement them beyond basic heterocyclic replacements. A benzofuran structural alert was successfully replaced with a 4-chlorophenyl group, and the addition of a cyclopropyl group to the oxadiazine core appeared to dramatically improve metabolic stability while maintaining potency and physicochemical properties, making it evidently worth dealing with the additional stereocenter. It is unlikely that the property improvements found with the oxadiazine could have been found on an amide-based scaffold. The molecule demonstrates PD in multiple species, was clean in numerous in vitro and in vivo toxicology experiments,…