6 research outputs found
Selective Inhibition of ICAM-1 and E-Selectin Expression in Human Endothelial Cells. 2. Aryl Modifications of 4-(Aryloxy)thieno[2,3- c
Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species
A hallmark of Alzheimer\u27s disease is the brain deposition of amyloid beta (Aβ), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Aβ is produced by the sequential cleavage of APP by BACE1 and γ-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer\u27s disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Aβ in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Aβ lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Aβ in rodents and in monkey. © 2013 American Chemical Society
Discovery of Inhibitors of Cell Adhesion Molecule Expression in Human Endothelial Cells. 1. Selective Inhibition of ICAM-1 and E-Selectin Expression
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
In an attempt to increase selectivity
vs Cathepsin D (CatD) in
our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyranoÂ[4,3-b]Âchromene
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 Aβ<sub>1–40</sub> production
(5–99 nM). They also suffered from high efflux. Despite this
undesirable property, two of the acyl guanidines achieved free brain
concentrations (C<sub>free,brain</sub>) in a guinea pig PD model sufficient
to cover their cell IC<sub>50</sub>s. Moreover, a significant reduction
of Aβ<sub>1–40</sub> in guinea pig, rat, and cyno CSF
(58%, 53%, and 63%, respectively) was observed for compound <b>62</b>