9 research outputs found
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
Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase
This paper describes the design and synthesis of a novel
series
of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2).
Key findings include the discovery of an initial lead that was modestly
potent and subsequent medicinal chemistry optimization with a focus
on lipophilic efficiency (LipE) to balance overall druglike properties.
Free-Wilson methodology provided a clear breakdown of the contributions
of specific structural elements to the overall LipE, a rationale for
prioritization of virtual compounds for synthesis, and a highly successful
prediction of the LipE of the resulting analogues. Further preclinical
assays, including in vivo malonyl-CoA reduction in both rat liver
(ACC1) and rat muscle (ACC2), identified an advanced analogue that
progressed to regulatory toxicity studies
Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor
A compact and stable bicyclic bridged
ketal was developed as a
ligand for the asialoglycoprotein receptor (ASGPR). This compound
showed excellent ligand efficiency, and the molecular details of binding
were revealed by the first X-ray crystal structures of ligand-bound
ASGPR. This analogue was used to make potent di- and trivalent binders
of ASGPR. Extensive characterization of the function of these compounds
showed rapid ASGPR-dependent cellular uptake in vitro and high levels
of liver/plasma selectivity in vivo. Assessment of the biodistribution
in rodents of a prototypical Alexa647-labeled trivalent conjugate
showed selective hepatocyte targeting with no detectable distribution
in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed
hepatocellular uptake and prolonged retention compared to a similar
GalNAc derived trimer conjugate. Selective release in the liver of
a passively permeable small-molecule cargo was achieved by retro-DielsāAlder
cleavage of an oxanorbornadiene linkage, presumably upon encountering
intracellular thiol. Therefore, the multicomponent construct described
here represents a highly efficient delivery vehicle to hepatocytes
Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor
A compact and stable bicyclic bridged
ketal was developed as a
ligand for the asialoglycoprotein receptor (ASGPR). This compound
showed excellent ligand efficiency, and the molecular details of binding
were revealed by the first X-ray crystal structures of ligand-bound
ASGPR. This analogue was used to make potent di- and trivalent binders
of ASGPR. Extensive characterization of the function of these compounds
showed rapid ASGPR-dependent cellular uptake in vitro and high levels
of liver/plasma selectivity in vivo. Assessment of the biodistribution
in rodents of a prototypical Alexa647-labeled trivalent conjugate
showed selective hepatocyte targeting with no detectable distribution
in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed
hepatocellular uptake and prolonged retention compared to a similar
GalNAc derived trimer conjugate. Selective release in the liver of
a passively permeable small-molecule cargo was achieved by retro-DielsāAlder
cleavage of an oxanorbornadiene linkage, presumably upon encountering
intracellular thiol. Therefore, the multicomponent construct described
here represents a highly efficient delivery vehicle to hepatocytes
Discovery and Preclinical Characterization of 6āChloro-5-[4-(1-hydroxycyclobutyl)phenyl]ā1<i>H</i>āindole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy
Adenosine
monophosphate-activated protein kinase (AMPK) is a protein
kinase involved in maintaining energy homeostasis within cells. On
the basis of human genetic association data, AMPK activators were
pursued for the treatment of diabetic nephropathy. Identification
of an indazole amide high throughput screening (HTS) hit followed
by truncation to its minimal pharmacophore provided an indazole acid
lead compound. Optimization of the core and aryl appendage improved
oral absorption and culminated in the identification of indole acid,
PF-06409577 (<b>7</b>). Compound <b>7</b> was advanced
to first-in-human trials for the treatment of diabetic nephropathy
Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)
Increased
fructose consumption and its subsequent metabolism have
been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin
resistance in humans. Since ketohexokinase (KHK) is the principal
enzyme responsible for fructose metabolism, identification of a selective
KHK inhibitor may help to further elucidate the effect of KHK inhibition
on these metabolic disorders. Until now, studies on KHK inhibition
with small molecules have been limited due to the lack of viable in
vivo pharmacological tools. Herein we report the discovery of <b>12</b>, a selective KHK inhibitor with potency and properties
suitable for evaluating KHK inhibition in rat models. Key structural
features interacting with KHK were discovered through fragment-based
screening and subsequent optimization using structure-based drug design,
and parallel medicinal chemistry led to the identification of pyridine <b>12</b>
Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5ā²-Adenosine Monophosphate-Activated Protein Kinase (AMPK)
Optimization
of the pharmacokinetic (PK) properties of a series
of activators of adenosine monophosphate-activated protein kinase
(AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic
acid clinical candidate (<b>1</b>) were examined with the goal
of reducing glucuronidation rate and minimizing renal excretion. Compounds <b>10</b> (PF-06679142) and <b>14</b> (PF-06685249) exhibited
robust activation of AMPK in rat kidneys as well as desirable oral
absorption, low plasma clearance, and negligible renal clearance in
preclinical species. A correlation of in vivo renal clearance in rats
with in vitro uptake by human and rat renal organic anion transporters
(human OAT/rat Oat) was identified. Variation of polar functional
groups was critical to mitigate active renal clearance mediated by
the Oat3 transporter. Modification of either the 6-chloroindole core
to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted
5-(3-pyridyl) group provided improved metabolic stability while minimizing
propensity for active transport by OAT3
Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5ā²-Adenosine Monophosphate-Activated Protein Kinase (AMPK)
Optimization
of the pharmacokinetic (PK) properties of a series
of activators of adenosine monophosphate-activated protein kinase
(AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic
acid clinical candidate (<b>1</b>) were examined with the goal
of reducing glucuronidation rate and minimizing renal excretion. Compounds <b>10</b> (PF-06679142) and <b>14</b> (PF-06685249) exhibited
robust activation of AMPK in rat kidneys as well as desirable oral
absorption, low plasma clearance, and negligible renal clearance in
preclinical species. A correlation of in vivo renal clearance in rats
with in vitro uptake by human and rat renal organic anion transporters
(human OAT/rat Oat) was identified. Variation of polar functional
groups was critical to mitigate active renal clearance mediated by
the Oat3 transporter. Modification of either the 6-chloroindole core
to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted
5-(3-pyridyl) group provided improved metabolic stability while minimizing
propensity for active transport by OAT3