Discovery of 7-Tetrahydropyran-2-yl Chromans: β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) inhibitors That Reduce Amyloid β-Protein (Aβ) in the Central Nervous System

被引：29

作者：

Thomas, Allen A. ^{[1
]}

Hunt, Kevin W. ^{[1
]}

Volgraf, Matthew ^{[2
]}

Watts, Ryan J. ^{[2
]}

Liu, Xingrong ^{[2
]}

Vigers, Guy ^{[1
]}

Smith, Darin ^{[1
]}

Sammond, Douglas ^{[1
]}

Tang, Tony P. ^{[1
]}

Rhodes, Susan P. ^{[1
]}

Metcalf, Andrew T. ^{[1
]}

Brown, Karin D. ^{[1
]}

Otten, Jennifer N. ^{[1
]}

Burkard, Michael ^{[1
]}

Cox, April A. ^{[1
]}

Do, Mary K. Geck ^{[1
]}

Dutcher, Darrin ^{[1
]}

Rana, Sumeet ^{[1
]}

DeLisle, Robert K. ^{[1
]}

Regal, Kelly ^{[1
]}

Wright, Albion D. ^{[1
]}

Groneberg, Robert ^{[1
]}

Scearce-Levie, Kimberly ^{[2
]}

Siu, Michael ^{[2
]}

Purkey, Hans E. ^{[2
]}

Lyssikatos, Joseph P. ^{[2
]}

Gunawardana, Indrani W. ^{[1
]}

机构：

[1] Array BioPharma, Boulder, CO 80301 USA

[2] Genentech Inc, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 03期

关键词：

ALZHEIMERS-DISEASE; HETERODIENE CYCLOADDITIONS; SECRETASE INHIBITORS; IODINE ISOCYANATE; BRAIN; DESIGN; CLEAVAGE; MODEL; AMINOIMIDAZOLES; IDENTIFICATION;

D O I：

10.1021/jm401635n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2' sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring A beta(1-40) production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (C-free,C-brain) in a guinea pig PD model sufficient to cover their cell IC(50)s. Moreover, a significant reduction of A beta(1-40) in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.

引用

页码：878 / 902

页数：25

共 56 条

[1]

[Anonymous], ALZHEIMERS DEMENTI S

[2] Synthesis of Some New Naphthopyran, Pyrazole, Pyridine, and Thienobenzochromene Derivatives Using 1-(1-Hydroxy-2-naphthyl) Ethanone as a Versatile Starting Material [J].