12 research outputs found
Selective inhibitors of the PSEN1-gamma-secretase complex
Clinical development of Y-secretases, a family of intramembrane cleaving proteases, as therapeutic targets for a variety of disorders including cancer and Alzheimer’s disease was aborted because of serious mechanism-based side effects in the phase III trials of unselective inhibitors. Selective inhibition of specific Y-secretase complexes, containing either PSEN1 or PSEN2 as the catalytic subunit and APH1A or APH1B as supporting subunits, does provide a feasible therapeutic window in preclinical models of these disorders. We explore here the pharmacophoric features required for PSEN1 versus PSEN2 selective inhibition. We synthesized a series of brain penetrant 2-azabicyclo[2,2,2]octane sulfonamides and identified a compound with low nanomolar potency and high selectivity (>250-fold) toward the PSEN1–APH1B subcomplex versus PSEN2 subcomplexes. We used modeling and site-directed mutagenesis to identify critical amino acids along the entry part of this inhibitor into the catalytic site of PSEN1. Specific targeting one of the different Y-secretase complexes might provide safer drugs in the future.The work was supported by an AIO-project (no. HBC.2016.0884). This project received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. ERC-834682 CELLPHASE_AD). This work was supported by the Flanders Institute for Biotechnology (VIB vzw), a Methusalem grant from KU Leuven and the Flemish Government, the Fonds voor Wetenschappelijk Onderzoek, KU Leuven, The Queen Elisabeth Medical Foundation for Neurosciences, the Opening the Future campaign of the Leuven Universitair Fonds, the Belgian Alzheimer Research Foundation (SAO-FRA), and the Alzheimer’s Association
USA.Peer ReviewedPostprint (published version
-Secretase Modulators: Can We Combine Potency with Safety?
-Secretase modulation has been proposed as a potential disease modifying anti-Alzheimer’s approach. -Secretase modulators (GSMs) cause a product shift from the longer amyloid-beta (Aβ) peptide isoforms to shorter, more soluble, and less amyloidogenic isoforms, without inhibiting APP or Notch proteolytic processing. As such, modulating -secretase may avoid some of the adverse effects observed with -secretase inhibitors. Since the termination of the GSM tarenfurbil in 2008 due to negative phase III trial results, a considerable progress has been made towards more potent and better brain penetrable compounds. However, an analysis of their lipophilic efficiency indices indicates that their increased potency can be largely attributed to their increased lipophilicity. The need for early and chronic dosing with GSMs will require high-safety margins. This will be a challenge to achieve with the current, highly lipophilic GSMs. We will demonstrate that by focusing on the drug-like properties of GSMs, a combination of high in vitro potency and reduced lipophilicity can be achieved and does result in better tolerated compounds. The next hurdle will be to translate this knowledge into GSMs which are highly efficacious and safe in vivo
Design and Synthesis of a Novel Series of Bicyclic Heterocycles As Potent γ-Secretase Modulators
The design and the synthesis of several chemical subclasses
of
imidazole containing γ-secretase modulators (GSMs) is described.
Conformational restriction of pyridone <b>4</b> into bicyclic
pyridone isosteres has led to compounds with high in vitro and in
vivo potency. This has resulted in the identification of benzimidazole <b>44a</b> as a GSM with low nanomolar potency in vitro. In mouse,
rat, and dog, this compound displayed the typical γ-secretase
modulatory profile by lowering Aβ42 and Aβ40 levels combined
with an especially pronounced increase in Aβ38 and Aβ37
levels while leaving the total levels of amyloid peptides unchanged
Optimization of 1,4-Oxazine β‑Secretase 1 (BACE1) Inhibitors Toward a Clinical Candidate
In previous studies,
the introduction of electron withdrawing groups
to 1,4-oxazine BACE1 inhibitors reduced the p<i>K</i><sub>a</sub> of the amidine group, resulting in compound <b>2</b> that showed excellent in vivo efficacy, lowering Aβ levels
in brain and CSF. However, a suboptimal cardiovascular safety margin,
based on QTc prolongation, prevented further progression. Further
optimization resulted in the replacement of the 2-fluoro substituent
by a CF<sub>3</sub>-group, which reduced hERG inhibition. This has
led to compound <b>3</b>, with an improved cardiovascular safety
margin and sufficiently safe in GLP toxicity studies to progress into
clinical trials
Discovery of Potent and Centrally Active 6‑Substituted 5‑Fluoro-1,3-dihydro-oxazine β‑Secretase (BACE1) Inhibitors via Active Conformation Stabilization
β-Secretase
(BACE1) has an essential role in the production
of amyloid β peptides that accumulate in patients with Alzheimer’s
disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying
approach for the treatment of AD. Our hit-to-lead efforts led to a
cellular potent 1,3-dihydro-oxazine <b>6</b>, which however
inhibited hERG and showed high P-gp efflux. The close analogue of
5-fluoro-oxazine <b>8</b> reduced P-gp efflux; further introduction
of electron withdrawing groups at the 6-position improved potency
and also mitigated P-gp efflux and hERG inhibition. Changing to a
pyrazine followed by optimization of substituents on both the oxazine
and the pyrazine culminated in <b>24</b> with robust Aβ
reduction in vivo at low doses as well as reduced CYP2D6 inhibition.
On the basis of the X-ray analysis and the QM calculation of given
dihydro-oxazines, we reasoned that the substituents at the 6-position
as well as the 5-fluorine on the oxazine would stabilize a bioactive
conformation to increase potency
Discovery of Potent and Centrally Active 6‑Substituted 5‑Fluoro-1,3-dihydro-oxazine β‑Secretase (BACE1) Inhibitors via Active Conformation Stabilization
β-Secretase
(BACE1) has an essential role in the production
of amyloid β peptides that accumulate in patients with Alzheimer’s
disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying
approach for the treatment of AD. Our hit-to-lead efforts led to a
cellular potent 1,3-dihydro-oxazine <b>6</b>, which however
inhibited hERG and showed high P-gp efflux. The close analogue of
5-fluoro-oxazine <b>8</b> reduced P-gp efflux; further introduction
of electron withdrawing groups at the 6-position improved potency
and also mitigated P-gp efflux and hERG inhibition. Changing to a
pyrazine followed by optimization of substituents on both the oxazine
and the pyrazine culminated in <b>24</b> with robust Aβ
reduction in vivo at low doses as well as reduced CYP2D6 inhibition.
On the basis of the X-ray analysis and the QM calculation of given
dihydro-oxazines, we reasoned that the substituents at the 6-position
as well as the 5-fluorine on the oxazine would stabilize a bioactive
conformation to increase potency