5 research outputs found
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
Rational Design of Novel 1,3-Oxazine Based β‑Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P‑gp Efflux Leading to Robust Aβ Reduction in the Brain
Accumulation of Aβ
peptides is a hallmark of Alzheimer’s
disease (AD) and is considered a causal factor in the pathogenesis
of AD. β-Secretase (BACE1) is a key enzyme responsible for producing
Aβ peptides, and thus agents that inhibit BACE1 should be beneficial
for disease-modifying treatment of AD. Here we describe the discovery
and optimization of novel oxazine-based BACE1 inhibitors by lowering
amidine basicity with the incorporation of a double bond to improve
brain penetration. Starting from a 1,3-dihydrooxazine lead <b>6</b> identified by a hit-to-lead SAR following HTS, we adopted a p<i>K</i><sub>a</sub> lowering strategy to reduce the P-gp efflux
and the high hERG potential leading to the discovery of <b>15</b> that produced significant Aβ reduction with long duration
in pharmacodynamic models and exhibited wide safety margins in cardiovascular
safety models. This compound improved the brain-to-plasma ratio relative
to <b>6</b> by reducing P-gp recognition, which was demonstrated
by a P-gp knockout mouse model
Rational Design of Novel 1,3-Oxazine Based β‑Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P‑gp Efflux Leading to Robust Aβ Reduction in the Brain
Accumulation of Aβ
peptides is a hallmark of Alzheimer’s
disease (AD) and is considered a causal factor in the pathogenesis
of AD. β-Secretase (BACE1) is a key enzyme responsible for producing
Aβ peptides, and thus agents that inhibit BACE1 should be beneficial
for disease-modifying treatment of AD. Here we describe the discovery
and optimization of novel oxazine-based BACE1 inhibitors by lowering
amidine basicity with the incorporation of a double bond to improve
brain penetration. Starting from a 1,3-dihydrooxazine lead <b>6</b> identified by a hit-to-lead SAR following HTS, we adopted a p<i>K</i><sub>a</sub> lowering strategy to reduce the P-gp efflux
and the high hERG potential leading to the discovery of <b>15</b> that produced significant Aβ reduction with long duration
in pharmacodynamic models and exhibited wide safety margins in cardiovascular
safety models. This compound improved the brain-to-plasma ratio relative
to <b>6</b> by reducing P-gp recognition, which was demonstrated
by a P-gp knockout mouse model