10 research outputs found
Getting the MAX out of Computational Models: The Prediction of Unbound-Brain and Unbound-Plasma Maximum Concentrations
The objective of this work was to establish that unbound
maximum
concentrations may be reasonably predicted from a combination of computed
molecular properties assuming subcutaneous (SQ) dosing. Additionally,
we show that the maximum unbound plasma and brain concentrations may
be projected from a mixture of in vitro absorption, distribution,
metabolism, excretion experimental parameters in combination with
computed properties (volume of distribution, fraction unbound in microsomes).
Finally, we demonstrate the utility of the underlying equations by
showing that the maximum total plasma concentrations can be projected
from the experimental parameters for a set of compounds with data
collected from clinical research
Getting the MAX out of Computational Models: The Prediction of Unbound-Brain and Unbound-Plasma Maximum Concentrations
The objective of this work was to establish that unbound
maximum
concentrations may be reasonably predicted from a combination of computed
molecular properties assuming subcutaneous (SQ) dosing. Additionally,
we show that the maximum unbound plasma and brain concentrations may
be projected from a mixture of in vitro absorption, distribution,
metabolism, excretion experimental parameters in combination with
computed properties (volume of distribution, fraction unbound in microsomes).
Finally, we demonstrate the utility of the underlying equations by
showing that the maximum total plasma concentrations can be projected
from the experimental parameters for a set of compounds with data
collected from clinical research
Getting the MAX out of Computational Models: The Prediction of Unbound-Brain and Unbound-Plasma Maximum Concentrations
The objective of this work was to establish that unbound
maximum
concentrations may be reasonably predicted from a combination of computed
molecular properties assuming subcutaneous (SQ) dosing. Additionally,
we show that the maximum unbound plasma and brain concentrations may
be projected from a mixture of in vitro absorption, distribution,
metabolism, excretion experimental parameters in combination with
computed properties (volume of distribution, fraction unbound in microsomes).
Finally, we demonstrate the utility of the underlying equations by
showing that the maximum total plasma concentrations can be projected
from the experimental parameters for a set of compounds with data
collected from clinical research
Measurement of Atropisomer Racemization Kinetics Using Segmented Flow Technology
When stable atropisomers are encountered by drug discovery
teams,
they can have important implications due to potential differences
in their biological activity, pharmacokinetics, and toxicity. Knowledge
of an atropisomer's activation parameters for interconversion is required
to facilitate informed decisions on how to proceed. Herein, we communicate
the development of a new method for the rapid measurement of atropisomer
racemization kinetics utilizing segmented flow technology. This method
leverages the speed, accuracy, low sample requirement, safety, and
semiautomated nature of flow instrumentation to facilitate the acquisition
of kinetics data required for experimentally probing atropisomer activation
parameters. Measured kinetics data obtained for the atropo isomerization
of AMPA antagonist CP-465021 using segmented flow and traditional
thermal methods were compared to validate the method
Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template
In this paper, we describe a lead transformation tool,
NEAT (<u>N</u>ovel and <u>E</u>lectronically
equivalent <u>A</u>romatic <u>T</u>emplate), which can
help identify novel aromatic rings that are estimated to have similar
electrostatic potentials, dipoles, and hydrogen bonding capabilities
to a query template; hence, they may offer similar bioactivity profiles.
In this work, we built a comprehensive heteroaryl database, and precalculated
high-level quantum mechanical (QM) properties, including electrostatic
potential charges, hydrogen bonding ability, dipole moments, chemical
reactivity, and othe properties. NEAT bioisosteric similarities are
based on the electrostatic potential surface calculated by Brood,
using the precalculated QM ESP charges and other QM properties. Compared
with existing commercial lead transformation software, (1) NEAT is
the only one that covers the comprehensive heteroaryl chemical space,
and (2) NEAT offers a better characterization of novel aryl cores
by using high-evel QM properties that are relevant to molecular interactions.
NEAT provides unique value to medicinal chemists quickly exploring
the largely uncharted aromatic chemical space, and one successful
example of its application is discussed herein
Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template
In this paper, we describe a lead transformation tool,
NEAT (<u>N</u>ovel and <u>E</u>lectronically
equivalent <u>A</u>romatic <u>T</u>emplate), which can
help identify novel aromatic rings that are estimated to have similar
electrostatic potentials, dipoles, and hydrogen bonding capabilities
to a query template; hence, they may offer similar bioactivity profiles.
In this work, we built a comprehensive heteroaryl database, and precalculated
high-level quantum mechanical (QM) properties, including electrostatic
potential charges, hydrogen bonding ability, dipole moments, chemical
reactivity, and othe properties. NEAT bioisosteric similarities are
based on the electrostatic potential surface calculated by Brood,
using the precalculated QM ESP charges and other QM properties. Compared
with existing commercial lead transformation software, (1) NEAT is
the only one that covers the comprehensive heteroaryl chemical space,
and (2) NEAT offers a better characterization of novel aryl cores
by using high-evel QM properties that are relevant to molecular interactions.
NEAT provides unique value to medicinal chemists quickly exploring
the largely uncharted aromatic chemical space, and one successful
example of its application is discussed herein
Casein Kinase 1δ/ε Inhibitor PF-5006739 Attenuates Opioid Drug-Seeking Behavior
Casein
kinase 1 delta (CK1δ) and casein kinase 1 epsilon
(CK1ε) inhibitors are potential therapeutic agents for a range
of psychiatric disorders. The feasibility of developing a CNS kinase
inhibitor has been limited by an inability to identify safe brain-penetrant
compounds with high kinome selectivity. Guided by structure-based
drug design, potent and selective CK1δ/ε inhibitors have
now been identified that address this gap, through the design and
synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1<i>H</i>-imidazol-5-yl]Âpyrimidin-2-amine derivatives. PF-5006739
(<b>6</b>) possesses a desirable profile, with low nanomolar
in vitro potency for CK1δ/ε (IC<sub>50</sub> = 3.9 and
17.0 nM, respectively) and high kinome selectivity. In vivo, <b>6</b> demonstrated robust centrally mediated circadian rhythm
phase-delaying effects in both nocturnal and diurnal animal models.
Further, <b>6</b> dose-dependently attenuated opioid drug-seeking
behavior in a rodent operant reinstatement model in animals trained
to self-administer fentanyl. Collectively, our data supports further
development of <b>6</b> as a promising candidate to test the
hypothesis of CK1δ/ε inhibition in treating multiple indications
in the clinic
Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase
Monoacylglycerol
lipase (MAGL) is the main enzyme responsible for
degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in
the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid
(AA), a precursor to the proinflammatory eicosannoids such as prostaglandins.
Herein we describe highly efficient MAGL inhibitors, identified through
a parallel medicinal chemistry approach that highlighted the improved
efficiency of azetidine and piperidine-derived carbamates. The discovery
and optimization of 3-substituted azetidine carbamate irreversible
inhibitors of MAGL were aided by the generation of inhibitor-bound
MAGL crystal structures. Compound <b>6</b>, a highly efficient
and selective MAGL inhibitor against recombinant enzyme and in a cellular
context, was tested in vivo and shown
to elevate central 2-AG levels at a 10 mg/kg dose
Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor
Phosphodiesterase 2A (PDE2A) inhibitors
have been reported to demonstrate
in vivo activity in preclinical models of cognition. To more fully
explore the biology of PDE2A inhibition, we sought to identify potent
PDE2A inhibitors with improved brain penetration as compared to current
literature compounds. Applying estimated human dose calculations while
simultaneously leveraging synthetically enabled chemistry and structure-based
drug design has resulted in a highly potent, selective, brain penetrant
compound <b>71</b> (PF-05085727) that effects in vivo biochemical
changes commensurate with PDE2A inhibition along with behavioral and
electrophysiological reversal of the effects of NMDA antagonists in
rodents. This data supports the ability of PDE2A inhibitors to potentiate
NMDA signaling and their further development for clinical cognition
indications
Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor
Phosphodiesterase 2A (PDE2A) inhibitors
have been reported to demonstrate
in vivo activity in preclinical models of cognition. To more fully
explore the biology of PDE2A inhibition, we sought to identify potent
PDE2A inhibitors with improved brain penetration as compared to current
literature compounds. Applying estimated human dose calculations while
simultaneously leveraging synthetically enabled chemistry and structure-based
drug design has resulted in a highly potent, selective, brain penetrant
compound <b>71</b> (PF-05085727) that effects in vivo biochemical
changes commensurate with PDE2A inhibition along with behavioral and
electrophysiological reversal of the effects of NMDA antagonists in
rodents. This data supports the ability of PDE2A inhibitors to potentiate
NMDA signaling and their further development for clinical cognition
indications