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

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posted on 03.03.2016, 00:00 by Mihirbaran Mandal, Yusheng Wu, Jeffrey Misiaszek, Guoqing Li, Alexei Buevich, John P. Caldwell, Xiaoxiang Liu, Robert D. Mazzola, Peter Orth, Corey Strickland, Johannes Voigt, Hongwu Wang, Zhaoning Zhu, Xia Chen, Michael Grzelak, Lynn A. Hyde, Reshma Kuvelkar, Prescott T. Leach, Giuseppe Terracina, Lili Zhang, Qi Zhang, Maria S. Michener, Brad Smith, Kathleen Cox, Diane Grotz, Leonard Favreau, Kaushik Mitra, Irina Kazakevich, Brian A. McKittrick, William Greenlee, Matthew E. Kennedy, Eric M. Parker, Jared N. Cumming, Andrew W. Stamford
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.