11 research outputs found
Speech Recognition Using Dynamical Model of Speech Production
We propose a speech recognition method based on the dynamical model of speech production. The model consists of an articulator and its control command sequences. The latter has linguistic information of speech and the former has the articulatory information which determines transformation from linguistic intentions to speech signals. This separation makes our speech recognition model more controllable. It provides new approaches to speaker adaptation and to coarticulation modeling. The effectiveness of the proposed model was examined by speaker-dependent letter recognition experiments. Visiting Scientist from C & C Information Technology Research Laboratories, NEC Corporation, 4-1-1 Miyazaki, Miyamae-ku, Kawasaki 216, JAPAN Keywords: speech recognition, neural networks, nonlinear prediction, hidden markov models, speaker adaptation Contents 1 Introduction 2 2 Model 2 3 Training Algorithms 4 4 Experimental Evaluation 6 5 Discussion and Conclusion 7 List of Figures 1 Model Architec..
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