5HDZ

BACE-1 in complex with (7aR)-7a-(5-cyanothiophen-2-yl)-6-(5-fluoro-4-methyl-6-(methylthio)pyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium

Summary for 5HDZ

• Entry DOI: 10.2210/pdb5hdz/pdb
• Related: 5HD0 5HDU 5HDV 5HDX 5HE4 5HE5 5HE7
• Descriptor: Beta-secretase 1, 5-{(2E,4aR,7aR)-6-[5-fluoro-4-methyl-6-(methylsulfanyl)pyrimidin-2-yl]-2-imino-3-methyl-4-oxooctahydro-7aH-pyrrolo[3,4-d]pyrimidin-7a-yl}thiophene-2-carbonitrile (3 entities in total)
• Functional Keywords: alzheimer's, aspartyl protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 2
• Total formula weight: 93362.87

Authors

Orth, P. (deposition date: 2016-01-05, release date: 2016-03-16, Last modification date: 2024-11-06)

Primary citation

Mandal, M.,Wu, Y.,Misiaszek, J.,Li, G.,Buevich, A.,Caldwell, J.P.,Liu, X.,Mazzola, R.D.,Orth, P.,Strickland, C.,Voigt, J.,Wang, H.,Zhu, Z.,Chen, X.,Grzelak, M.,Hyde, L.A.,Kuvelkar, R.,Leach, P.T.,Terracina, G.,Zhang, L.,Zhang, Q.,Michener, M.S.,Smith, B.,Cox, K.,Grotz, D.,Favreau, L.,Mitra, K.,Kazakevich, I.,McKittrick, B.A.,Greenlee, W.,Kennedy, M.E.,Parker, E.M.,Cumming, J.N.,Stamford, A.W.
Structure-Based Design of an Iminoheterocyclic beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central A beta in Nonhuman Primates.
J.Med.Chem., 59:3231-3248, 2016

PubMed 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.

PubMed: 26937601
DOI: 10.1021/acs.jmedchem.5b01995

Experimental method

X-RAY DIFFRACTION (1.49 Å)