National Center for
5HDX: Bace-1 In Complex With (7ar)-7a-(5-cyanothiophen-2-yl)-6-(4-ethoxy-5- Fluoro-6-methylpyrimidin-2-yl)-3-methyl-4-oxooctahydro-2h-pyrrolo[3, 4-d]pyrimidin-2-iminium
Structure-Based Design of an Iminoheterocyclic beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Abeta in Nonhuman Primates
J. Med. Chem. (2016) 59 p.3231-3248
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 Abeta40 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 Abeta in nonrodent preclinical species.