5YGY

Crystal Structure of BACE1 in complex with (S)-N-(3-(2-amino-6-(fluoromethyl)-4 -methyl-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide

Summary for 5YGY

• Entry DOI: 10.2210/pdb5ygy/pdb
• Descriptor: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: beta-site amyloid precursor protein cleaving enzyme 1, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 47687.20

Authors

Fuchino, K.,Mitsuoka, Y.,Masui, M.,Kurose, N.,Yoshida, S.,Komano, K.,Yamamoto, T.,Ogawa, M.,Unemura, C.,Hosono, M.,Ito, H.,Sakaguchi, G.,Ando, S.,Ohnishi, S.,Kido, Y.,Fukushima, T.,Miyajima, H.,Hiroyama, S.,Koyabu, K.,Dhuyvetter, D.,Borghys, H.,Gijsen, H.,Yamano, Y.,Iso, Y.,Kusakabe, K. (deposition date: 2017-09-27, release date: 2018-05-23, Last modification date: 2024-11-13)

Primary citation

Fuchino, K.,Mitsuoka, Y.,Masui, M.,Kurose, N.,Yoshida, S.,Komano, K.,Yamamoto, T.,Ogawa, M.,Unemura, C.,Hosono, M.,Ito, H.,Sakaguchi, G.,Ando, S.,Ohnishi, S.,Kido, Y.,Fukushima, T.,Miyajima, H.,Hiroyama, S.,Koyabu, K.,Dhuyvetter, D.,Borghys, H.,Gijsen, H.J.M.,Yamano, Y.,Iso, Y.,Kusakabe, K.I.
Rational Design of Novel 1,3-Oxazine Based beta-Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P-gp Efflux Leading to Robust A beta Reduction in the Brain
J. Med. Chem., 61:5122-5137, 2018

PubMed Abstract: Accumulation of Aβ peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. β-Secretase (BACE1) is a key enzyme responsible for producing Aβ peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a p K lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aβ reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.

PubMed: 29733614
DOI: 10.1021/acs.jmedchem.8b00002

Experimental method

X-RAY DIFFRACTION (2.3 Å)