New nitrogen-heterocycle fragments enable scaffold hop yielding an aripiprazole analog
- The authors prepared a dozen new or little-explored fused six-six nitrogen bicycles in short synthetic sequences, all meeting fragment-likeness criteria, and added them to an existing fragment collection.
- As a test of scaffold hopping, a naphthyridinol replaced the hydroxy-dihydroquinolinone core of aripiprazole.
- The resulting analog suppressed cocaine-induced hyperactivity in rodents without causing catalepsy, resembling the parent drug's profile and suggesting antipsychotic potential.
💡 Points
Swapping aripiprazole's hydroxy-dihydroquinolinone for a naphthyridinol adds a ring nitrogen, which should lower logD and open fresh IP space on a crowded core. The catch is that reversed cocaine hyperactivity without catalepsy is only a phenotypic readout; with no D2 partial agonism or 5-HT1A/2A data, it's unclear whether the hop preserved the pharmacology.