2. Academic Validation
  3. Discovery of Extremely Selective Fused Pyridine-Derived β-Site Amyloid Precursor Protein-Cleaving Enzyme (BACE1) Inhibitors with High In Vivo Efficacy through 10s Loop Interactions

Discovery of Extremely Selective Fused Pyridine-Derived β-Site Amyloid Precursor Protein-Cleaving Enzyme (BACE1) Inhibitors with High In Vivo Efficacy through 10s Loop Interactions

  • J Med Chem. 2021 Oct 14;64(19):14165-14174. doi: 10.1021/acs.jmedchem.1c00359.
Tatsuhiko Ueno 1,  Eriko Matsuoka 1,  Naoya Asada 1,  Shiho Yamamoto 1,  Naoki Kanegawa 2,  Mana Ito 3,  Hisanori Ito 3,  Diederik Moechars 4,  Frederik J R Rombouts 5,  Harrie J M Gijsen 5,  Ken-Ichi Kusakabe 1
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 2 Laboratory for Drug Discovery & Development, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 3 Laboratory for Drug Discovery & Disease Research, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
  • 4 Neuroscience, Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 5 Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
PMID: 34553947 DOI: 10.1021/acs.jmedchem.1c00359
Abstract

β-Site amyloid precursor protein-cleaving Enzyme 1 (BACE1) is considered to be a promising target for treating Alzheimer's disease. However, all clinical BACE1 inhibitors have failed due to lack of efficacy, and some have even led to cognitive worsening. Recent evidence points to the importance of avoiding BACE2 inhibition along with careful dose titration. In this study, we focused on the fact that the 10s loop lining the S3 pocket in BACE1 can form both "open (up)" and "closed (down)" conformations, whereas in BACE2, it prefers to adopt a "closed" form; thus, more space is available in BACE1. By leveraging the difference, we designed fused pyridine analogues that could reach the 10s loop, leading to 6 with high selectivity and significant Aβ reduction. The cocrystal structures confirmed that 6 significantly increased B-factors of the 10s loop in BACE2 relative to those in BACE1. Thus, the destabilization of BACE2 seems to offer structural insights into the reduced BACE2 potency of 6, explaining the significant improvement in BACE1 selectivity.

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