Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: design, synthesis and X-ray crystal structures of enzyme inhibitor complexes.
نویسندگان
چکیده
A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed.
منابع مشابه
Design and Synthesis of Inhibitors Targeting BACE-1, an Aspartic Protease Involved in the Pathogenesis of Alzheimer’s Disease
"Anyone who has never made a mistake has never tried anything new." Abstract Alzheimer's disease (AD) is the most common form of dementia, occurring in an estimated 24 million people worldwide. Accumulation of amyloid-β peptides leads to development of plaques in the brain, which eventually stimulates hyperphosphorylation of tau proteins leading to tangles. This is believed to play a crucial ro...
متن کاملDesign and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents
Novel BACE-1 inhibitors with a hydroxyethylene central core have been developed. Modified P1´ and extended P1 substituents were incorporated with the aim to explore potential interactions with the S1´ and the S1-S3 pocket, respectively, of BACE-1. Inhibitors were identified displaying IC50 values in the nanomolar range, i.e. 69 nM for the most potent compound. Possible inhibitor interactions wi...
متن کاملDesign, Synthesis and Biological Activity of 4,6-disubstituted Pyridin-2(1H)-ones as Novel Inhibitors of Soluble Epoxide Hydrolase
Soluble epoxide hydrolase enzyme is a promising therapeutic target for hypertension, vascular inflammation, pain and some other risk factors of cardiovascular diseases. The most potent sEH inhibitors reported in the literature are urea-based ones which often have poor bioavailability. In this study, in a quest for finding potent inhibitors of soluble epoxide hydrolase, some 4,6-disubstituted py...
متن کاملDesign, Synthesis and Biological Activity of 4,6-disubstituted Pyridin-2(1H)-ones as Novel Inhibitors of Soluble Epoxide Hydrolase
Soluble epoxide hydrolase enzyme is a promising therapeutic target for hypertension, vascular inflammation, pain and some other risk factors of cardiovascular diseases. The most potent sEH inhibitors reported in the literature are urea-based ones which often have poor bioavailability. In this study, in a quest for finding potent inhibitors of soluble epoxide hydrolase, some 4,6-disubstituted py...
متن کاملNew 16-membered macrocyclic Schiff base: Synthesis, structural and FT-IR studies
In this paper, the structure of a new 16-membered macrocyclic Schiff base compound N,N′-(3,3′-dimethoxy-2,2′-(propane-1,3-diyldioxy)dibenzylidene)propane-1,3-diamine, C22H26N2O4 (1), derived from 1,3-propanediamine and 3,3′-dimethoxy-2,2′-(propane-1,3-diyldioxy)dibenzaldehyde has been studied by single crystal X-ray diffraction, DFT calculations at B3LYP/6-31G** and FT-IR spectroscopy. The titl...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Bioorganic & medicinal chemistry
دوره 20 14 شماره
صفحات -
تاریخ انتشار 2012