학술논문
Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates.
Document Type
Article
Author
Mandal, Mihirbaran; Yusheng Wu; Misiaszek, Jeffrey; Guoqing Li; Buevich, Alexei; Caldwell, John P.; Xiaoxiang Liu; Mazzola, Robert D.; Orth, Peter; Strickland, Corey; Voigt, Johannes; Hongwu Wang; Zhaoning Zhu; Xia Chen; Grzelak, Michael; Hyde, Lynn A.; Kuvelkar, Reshma; Leach, Prescott T.; Terracina, Giuseppe; Lili Zhang
Source
Subject
*AMYLOID beta-protein precursor
*ENZYME inhibitors
*HETEROCYCLIC compounds
*PYRROLIDINE
*CEREBROSPINAL fluid
*MOLECULAR structure
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Language
ISSN
0022-2623
Abstract
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. [ABSTRACT FROM AUTHOR]