6 research outputs found
Evaluation and Characterization of Trk Kinase Inhibitors for the Treatment of Pain: Reliable Binding Affinity Predictions from Theory and Computation
Optimization
of ligand binding affinity to the target protein of
interest is a primary objective in small-molecule drug discovery.
Until now, the prediction of binding affinities by computational methods
has not been widely applied in the drug discovery process, mainly
because of its lack of accuracy and reproducibility as well as the
long turnaround times required to obtain results. Herein we report
on a collaborative study that compares tropomyosin receptor kinase
A (TrkA) binding affinity predictions using two recently formulated
fast computational approaches, namely, Enhanced Sampling of Molecular
dynamics with Approximation of Continuum Solvent (ESMACS) and Thermodynamic
Integration with Enhanced Sampling (TIES), to experimentally derived
TrkA binding affinities for a set of Pfizer pan-Trk compounds. ESMACS
gives precise and reproducible results and is applicable to highly
diverse sets of compounds. It also provides detailed chemical insight
into the nature of ligandāprotein binding. TIES can predict
and thus optimize more subtle changes in binding affinities between
compounds of similar structure. Individual binding affinities were
calculated in a few hours, exhibiting good correlations with the experimental
data of 0.79 and 0.88 from the ESMACS and TIES approaches, respectively.
The speed, level of accuracy, and precision of the calculations are
such that the affinity predictions can be used to rapidly explain
the effects of compound modifications on TrkA binding affinity. The
methods could therefore be used as tools to guide lead optimization
efforts across multiple prospective structurally enabled programs
in the drug discovery setting for a wide range of compounds and targets
Discovery of a Series of Indazole TRPA1 Antagonists
A series
of TRPA1 antagonists is described which has as its core
structure an indazole moiety. The physical properties and <i>in vitro</i> DMPK profiles are discussed. Good <i>in vivo</i> exposure was obtained with several analogs, allowing efficacy to
be assessed in rodent models of inflammatory pain. Two compounds showed
significant activity in these models when administered either systemically
or topically. Protein chimeras were constructed to indicate compounds
from the series bound in the S5 region of the channel, and a computational
docking model was used to propose a binding mode for example compounds
Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors
Tropomyosin receptor kinases (TrkA,
TrkB, TrkC) are activated by
hormones of the neurotrophin family: nerve growth factor (NGF), brain
derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin
4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical
proof of concept for inhibition of the TrkA kinase pathway in pain
leading to significant interest in the development of small molecule
inhibitors of TrkA. However, achieving TrkA subtype selectivity over
TrkB and TrkC via a Type I and Type II inhibitor binding mode has
proven challenging and Type III or Type IV allosteric inhibitors may
present a more promising selectivity design approach. Furthermore,
TrkA inhibitors with minimal brain availability are required to deliver
an appropriate safety profile. Herein, we describe the discovery of
a highly potent, subtype selective, peripherally restricted, efficacious,
and well-tolerated series of allosteric TrkA inhibitors that culminated
in the delivery of candidate quality compound <b>23</b>
Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors
Tropomyosin receptor kinases (TrkA,
TrkB, TrkC) are activated by
hormones of the neurotrophin family: nerve growth factor (NGF), brain
derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin
4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical
proof of concept for inhibition of the TrkA kinase pathway in pain
leading to significant interest in the development of small molecule
inhibitors of TrkA. However, achieving TrkA subtype selectivity over
TrkB and TrkC via a Type I and Type II inhibitor binding mode has
proven challenging and Type III or Type IV allosteric inhibitors may
present a more promising selectivity design approach. Furthermore,
TrkA inhibitors with minimal brain availability are required to deliver
an appropriate safety profile. Herein, we describe the discovery of
a highly potent, subtype selective, peripherally restricted, efficacious,
and well-tolerated series of allosteric TrkA inhibitors that culminated
in the delivery of candidate quality compound <b>23</b>
Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain
Hormones
of the neurotrophin family, nerve growth factor (NGF),
brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and
neurotrophin 4 (NT4), are known to activate the family of Tropomyosin
receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the
TrkA kinase pathway in pain has been clinically validated by the NGF
antibody tanezumab, leading to significant interest in the development
of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors
having an acceptable safety profile will require minimal brain availability.
Herein, we discuss the discovery of two potent, selective, peripherally
restricted, efficacious, and well-tolerated series of pan-Trk inhibitors
which successfully delivered three candidate quality compounds <b>10b</b>, <b>13b</b>, and <b>19</b>. All three compounds
are predicted to possess low metabolic clearance in human that does
not proceed via aldehyde oxidase-catalyzed reactions, thus addressing
the potential clearance prediction liability associated with our current
pan-Trk development candidate PF-06273340
Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain
Hormones
of the neurotrophin family, nerve growth factor (NGF),
brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and
neurotrophin 4 (NT4), are known to activate the family of Tropomyosin
receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the
TrkA kinase pathway in pain has been clinically validated by the NGF
antibody tanezumab, leading to significant interest in the development
of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors
having an acceptable safety profile will require minimal brain availability.
Herein, we discuss the discovery of two potent, selective, peripherally
restricted, efficacious, and well-tolerated series of pan-Trk inhibitors
which successfully delivered three candidate quality compounds <b>10b</b>, <b>13b</b>, and <b>19</b>. All three compounds
are predicted to possess low metabolic clearance in human that does
not proceed via aldehyde oxidase-catalyzed reactions, thus addressing
the potential clearance prediction liability associated with our current
pan-Trk development candidate PF-06273340