4 research outputs found
Benzazaborinines as Novel Bioisosteric Replacements of Naphthalene: Propranolol as an Example
Two benzazaborinine analogues of
propranolol were synthesized and
extensively profiled <i>in vitro</i> and <i>in vivo</i>. These analogues showed potency and physicochemical and <i>in vitro</i> ADMEātox profiles comparable to propranolol.
In addition, both benzazaborinine analogues showed excellent bioavailability
and brain penetration following subcutaneous administration in a pharmacokinetic
study in rats. These studies unveil the potential of aromatic azaborinines
as bioisosteric replacements of naphthalene in drug discovery programs
Optimization of 1,4-Oxazine Ī²āSecretase 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 AĪ² 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
1,4-Oxazine Ī²āSecretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads
1,4-Oxazines
are presented, which show good in vitro inhibition
in enzymatic and cellular BACE1 assays. We describe lead optimization
focused on reducing the amidine p<i>K</i><sub>a</sub> while
optimizing interactions in the BACE1 active site. Our strategy permitted
modulation of properties such as permeation and especially P-glycoprotein
efflux. This led to compounds which were orally bioavailable, centrally
active, and which demonstrated robust lowering of brain and CSF AĪ²
levels, respectively, in mouse and dog models. The amyloid lowering
potential of these molecules makes them valuable leads in the search
for new BACE1 inhibitors for the treatment of Alzheimerās disease
Discovery of <i>N</i>ā(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimerās Disease
A mini-HTS
on 4000 compounds selected using 2D fragment-based similarity
and 3D pharmacophoric and shape similarity to known selective tau
aggregate binders identified <i>N</i>-(6-methylpyridin-2-yl)Āquinolin-2-amine <b>10</b> as a novel potent binder to human AD aggregated tau with
modest selectivity versus aggregated Ī²-amyloid (AĪ²). Initial
medicinal chemistry efforts identified key elements for potency and
selectivity, as well as suitable positions for radiofluorination,
leading to a first generation of fluoroalkyl-substituted quinoline
tau binding ligands with suboptimal physicochemical properties. Further
optimization toward a more optimal pharmacokinetic profile led to
the discovery of 1,5-naphthyridine <b>75</b>, a potent and selective
tau aggregate binder with potential as a tau PET tracer