53001-75-5Relevant academic research and scientific papers
Unprecedented Reversal of Regioselectivity during Methanolysis and an Interception of Curtius Rearrangement
Brunskill, Andrew,Buevich, Alexei V.,Caldwell, John P.,Cumming, Jared,Liu, Xiaoxiang,Mandal, Mihirbaran,Mazzola, Robert,McKittrick, Brian,Orth, Peter,Stamford, Andrew,Wang, Hongwu,Zhu, Zhaoning
supporting information, p. 5073 - 5079 (2021/09/28)
Unprecedented reversal in regioselectivity during methanolysis of anhydrides due to the change in substitution pattern of fluorine in the phenyl moiety, and the formation of nitrene intercepted intermediates during Curtius rearrangement of the acids were the major impediments for discovering bioactive molecules in beta amyloid cleaving enzyme-1 (BACE1) program. Solutions to these synthetic challenges, and our investigation into this unexpected change in reactivity are discussed.
Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates
Mandal, Mihirbaran,Wu, Yusheng,Misiaszek, Jeffrey,Li, Guoqing,Buevich, Alexei,Caldwell, John P.,Liu, Xiaoxiang,Mazzola, Robert D.,Orth, Peter,Strickland, Corey,Voigt, Johannes,Wang, Hongwu,Zhu, Zhaoning,Chen, Xia,Grzelak, Michael,Hyde, Lynn A.,Kuvelkar, Reshma,Leach, Prescott T.,Terracina, Giuseppe,Zhang, Lili,Zhang, Qi,Michener, Maria S.,Smith, Brad,Cox, Kathleen,Grotz, Diane,Favreau, Leonard,Mitra, Kaushik,Kazakevich, Irina,McKittrick, Brian A.,Greenlee, William,Kennedy, Matthew E.,Parker, Eric M.,Cumming, Jared N.,Stamford, Andrew W.
, p. 3231 - 3248 (2016/05/19)
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.
