Toward β-Secretase-1 Inhibitors with Improved Isoform Selectivity

被引：24

作者：

Johansson, Patrik ^{[1
]}

Kaspersson, Karin ^{[1
]}

Gurrell, Ian K. ^{[2
]}

Back, Elisabeth ^{[1
]}

Eketjall, Susanna ^{[3
]}

Scott, Clay W. ^{[4
]}

Cebers, Gvido ^{[2
,8
]}

Thorne, Philip ^{[5
]}

McKenzie, Michael J. ^{[5
]}

Beaton, Haydn ^{[5
]}

Davey, Paul ^{[6
]}

Kolmodin, Karin ^{[7
]}

Holenz, Jorg ^{[2
]}

Duggan, Mark E. ^{[2
]}

Haeberlein, Samantha Budd ^{[2
,9
]}

Burli, Roland W. ^{[2
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Discovery Sci, S-43183 Molndal, Sweden

[2] AstraZeneca, IMED Biotech Unit, Neurosci, Cambridge CB21 6GH, England

[3] AstraZeneca, IMED Biotech Unit, Cardiovasc & Metab Dis, S-14157 Huddinge, Sweden

[4] AstraZeneca, IMED Biotech Unit, Discovery Safety Drug Safety & Metab, Waltham, MA 02451 USA

[5] Charnwood Mol, Loughborough LE11 5DA, Leics, England

[6] AstraZeneca, IMED Biotech Unit, Oncol Chem, Cambridge CB4 0WG, England

[7] Sprint Biosci, S-14157 Huddinge, Sweden

[8] UCB Biopharma, Chemin Foriest 1, B-1420 Braine Lalleud, Belgium

[9] Biogen, 225 Binney St, Cambridge, MA 02142 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 08期

关键词：

AMYLOID PRECURSOR PROTEIN; SECRETASE BACE-1 INHIBITORS; ALZHEIMERS-DISEASE; BETA-SECRETASE; A-BETA; CRYSTAL-STRUCTURE; DRUG DISCOVERY; APP GENE; MUTATION; OPTIMIZATION;

D O I：

10.1021/acs.jmedchem.7b01716

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

BACE1 is responsible for the first step in APP proteolysis, leading to toxic A beta 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 similar to 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.

引用

页码：3491 / 3502

页数：12

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