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J Med Chem. 2018 Apr 26;61(8):3491-3502. doi: 10.1021/acs.jmedchem.7b01716. Epub 2018 Apr 10.

Toward β-Secretase-1 Inhibitors with Improved Isoform Selectivity.

Author information

1
Discovery Sciences, IMED Biotech Unit , AstraZeneca , S-43183 Mölndal , Sweden.
2
Neuroscience, IMED Biotech Unit , AstraZeneca , Cambridge CB21 6GH , U.K.
3
Cardiovascular and Metabolic Diseases, IMED Biotech Unit , AstraZeneca , 141 57 Huddinge , Sweden.
4
Discovery Safety, Drug Safety and Metabolism, IMED Biotech Unit , AstraZeneca , Waltham , Massachusetts 02451 , United States.
5
Charnwood Molecular , Loughborough LE11 5DA , U.K.
6
Oncology Chemistry, IMED Biotech Unit , AstraZeneca , Cambridge CB4 0WG , U.K.
7
Sprint Bioscience , 141 57 Huddinge , Sweden.

Abstract

BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aβ production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited ∼50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class.

PMID:
29617572
DOI:
10.1021/acs.jmedchem.7b01716
[Indexed for MEDLINE]

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