Structure-Based Design of an Iminoheterocyclic β‑Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

We
describe successful efforts to optimize the in vivo profile and address
off-target liabilities of a series of BACE1 inhibitors represented
by 6 that embodies the recently validated fused pyrrolidine
iminopyrimidinone scaffold. Employing structure-based design, truncation
of the cyanophenyl group of 6 that binds in the S3 pocket
of BACE1 followed by modification of the thienyl group in S1 was pursued.
Optimization of the pyrimidine substituent that binds in the S2′–S2″
pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier
analogues in this series and imparted high BACE1 affinity. These efforts
resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a single oral dose.
Compound 9 represents a unique molecular shape among
BACE inhibitors reported to potently lower central Aβ in nonrodent
preclinical species.