10 research outputs found
A Novel Class of Succinimide-Derived Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 1 Provides Insight into a Disconnect in Activity between the Rat and Human Receptors
Recent
progress in the discovery of mGlu<sub>1</sub> allosteric
modulators has suggested the modulation of mGlu<sub>1</sub> could
offer possible treatment for a number of central nervous system disorders;
however, the available chemotypes are inadequate to fully investigate
the therapeutic potential of mGlu<sub>1</sub> modulation. To address
this issue, we used a fluorescence-based high-throughput screening
assay to screen an allosteric modulator-biased library of compounds
to generate structurally diverse mGlu<sub>1</sub> negative allosteric
modulator hits for chemical optimization. Herein, we describe the
discovery and characterization of a novel mGlu<sub>1</sub> chemotype.
This series of succinimide negative allosteric modulators, exemplified
by VU0410425, exhibited potent inhibitory activity at rat mGlu<sub>1</sub> but was, surprisingly, inactive at human mGlu<sub>1</sub>. VU0410425 and a set of chemically diverse mGlu<sub>1</sub> negative
allosteric modulators previously reported in the literature were utilized
to examine this species disconnect between rat and human mGlu<sub>1</sub> activity. Mutation of the key transmembrane domain residue
757 and functional screening of VU0410425 and the literature compounds
suggests that amino acid 757 plays a role in the activity of these
compounds, but the contribution of the residue is scaffold specific,
ranging from critical to minor. The operational model of allosterism
was used to estimate the binding affinities of each compound to compare
to functional data. This novel series of mGlu<sub>1</sub> negative
allosteric modulators provides valuable insight into the pharmacology
underlying the disconnect between rat and human mGlu<sub>1</sub> activity,
an issue that must be understood to progress the therapeutic potential
of allosteric modulators of mGlu<sub>1</sub>
Discovery of (<i>R</i>)‑(2-Fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-Hydroxypiperidin-1-yl)methanone (ML337), An mGlu<sub>3</sub> Selective and CNS Penetrant Negative Allosteric Modulator (NAM)
A multidimensional,
iterative parallel synthesis effort identified a series of highly
selective mGlu<sub>3</sub> NAMs with submicromolar potency and good CNS penetration.
Of these, ML337 resulted (mGlu<sub>3</sub> IC<sub>50</sub> = 593 nM,
mGlu<sub>2</sub> IC<sub>50</sub> >30 μM) with B:P ratios
of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to
the incorporation of deuterium atoms to address a metabolic soft spot,
which subsequently lowered both in vitro and in vivo clearance by
>50%
Substituted 1‑Phenyl-3-(pyridin-2-yl)urea Negative Allosteric Modulators of mGlu<sub>5</sub>: Discovery of a New Tool Compound VU0463841 with Activity in Rat Models of Cocaine Addiction
Cocaine
is a powerful and highly addictive stimulant that disrupts the normal
reward circuitry in the central nervous system (CNS), producing euphoric
effects. Cocaine use can lead to acute and life threatening emergencies,
and abuse is associated with increased risk for contracting infectious
diseases. Though certain types of behavioral therapy have proven effective
for treatment of cocaine addiction, relapse remains high, and there
are currently no approved medications for the treatment of cocaine
abuse. Evidence has continued to accumulate that indicates a critical
role for the metabotropic glutamate receptor subtype 5 (mGlu<sub>5</sub>) in the modulation of neural circuitry associated with the addictive
properties of cocaine. While the small molecule mGlu<sub>5</sub> negative
allosteric modulator (NAM) field is relatively advanced, investigation
into the potential of small molecule mGlu<sub>5</sub> NAMs for the
treatment of cocaine addiction remains an area of high interest. Herein
we describe the discovery and characterization of a potent and selective
compound <b>29</b> (VU0463841) with good CNS exposure in rats.
The utility of <b>29</b> (VU0463841) was demonstrated by its
ability to attenuate drug seeking behaviors in relevant rat models
of cocaine addiction
Design of 4‑Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2
Both
orthosteric and allosteric antagonists of the group II metabotropic
glutamate receptors (mGlus) have been used to establish a link between
mGlu<sub>2/3</sub> inhibition and a variety of CNS diseases and disorders.
Though these tools typically have good selectivity for mGlu<sub>2/3</sub> versus the remaining six members of the mGlu family, compounds that
are selective for only one of the individual group II mGlus have proved
elusive. Herein we report on the discovery of a potent and highly
selective mGlu<sub>2</sub> negative allosteric modulator <b>58</b> (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides.
The concept for the design of this series centered on morphing a quinoline
series recently disclosed in the patent literature into a chemotype
previously used for the preparation of muscarinic acetylcholine receptor
subtype 1 positive allosteric modulators. Compound <b>58</b> exhibits a favorable profile and will be a useful tool for understanding
the biological implications of selective inhibition of mGlu<sub>2</sub> in the CNS
Design and Synthesis of mGlu<sub>2</sub> NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core
Herein,
we detail the optimization of the mGlu<sub>2</sub> negative
allosteric modulator (NAM), VU6001192, by a reductionist approach
to afford a novel, simplified mGlu<sub>2</sub> NAM scaffold. This
new chemotype not only affords potent and selective mGlu<sub>2</sub> inhibition, as exemplified by VU6001966 (mGlu<sub>2</sub> IC<sub>50</sub> = 78 nM, mGlu<sub>3</sub> IC<sub>50</sub> > 30 μM),
but also excellent central nervous system (CNS) penetration (<i>K</i><sub>p</sub> = 1.9, <i>K</i><sub>p,uu</sub> =
0.78), a feature devoid in all previously disclosed mGlu<sub>2</sub> NAMs (<i>K</i><sub>p</sub>s ≈ 0.3, <i>K</i><sub>p,uu</sub>s ≈ 0.1). Moreover, this series, based on overall
properties, represents an exciting lead series for potential mGlu<sub>2</sub> PET tracer development
Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M<sub>1</sub> Positive Allosteric Modulators
This
Letter describes the chemical optimization of a new series
of muscarinic acetylcholine receptor subtype 1 (M<sub>1</sub>) positive
allosteric modulators (PAMs) based on novel tricyclic triazolo- and
imidazopyridine lactam cores, devoid of M<sub>1</sub> agonism, e.g.,
no M<sub>1</sub> ago-PAM activity, in high expressing recombinant
cell lines. While all the new tricyclic congeners afforded excellent
rat pharmacokinetic (PK) properties (CL<sub>p</sub> < 8 mL/min/kg
and <i>t</i><sub>1/2</sub> > 5 h), regioisomeric triazolopyridine
analogues were uniformly not CNS penetrant (<i>K</i><sub>p</sub> < 0.05), despite a lack of hydrogen bond donors. However,
removal of a single nitrogen atom to afford imidazopyridine derivatives
proved to retain the excellent rat PK and provide high CNS penetration
(<i>K</i><sub>p</sub> > 2), despite inclusion of a basic
nitrogen. Moreover, <b>24c</b> was devoid of M<sub>1</sub> agonism
in high expressing recombinant cell lines and did not induce cholinergic
seizures in vivo in mice. Interestingly, all of the new M<sub>1</sub> PAMs across the diverse tricyclic heterocyclic cores possessed equivalent
CNS MPO scores (>4.5), highlighting the value of both “medicinal
chemist’s eye” and experimental data, e.g., not sole
reliance (or decision bias) on in silico calculated properties, for
parameters as complex as CNS penetration
Identification of Specific Ligand–Receptor Interactions That Govern Binding and Cooperativity of Diverse Modulators to a Common Metabotropic Glutamate Receptor 5 Allosteric Site
A common
metabotropic glutamate receptor 5 (mGlu<sub>5</sub>) allosteric
site is known to accommodate diverse chemotypes. However, the structural
relationship between compounds from different scaffolds and mGlu<sub>5</sub> is not well understood. In an effort to better understand
the molecular determinants that govern allosteric modulator interactions
with mGlu<sub>5</sub>, we employed a combination of site-directed
mutagenesis and computational modeling. With few exceptions, six residues
(P654, Y658, T780, W784, S808, and A809) were identified as key affinity
determinants across all seven allosteric modulator scaffolds. To improve
our interpretation of how diverse allosteric modulators occupy the
common allosteric site, we sampled the wealth of mGlu<sub>5</sub> structure–activity
relationship (SAR) data available by docking 60 ligands (actives and
inactives) representing seven chemical scaffolds into our mGlu<sub>5</sub> comparative model. To spatially and chemically compare binding
modes of ligands from diverse scaffolds, the ChargeRMSD measure was
developed. We found a common binding mode for the modulators that
placed the long axes of the ligands parallel to the transmembrane
helices 3 and 7. W784 in TM6 not only was identified as a key NAM
cooperativity determinant across multiple scaffolds, but also caused
a NAM to PAM switch for two different scaffolds. Moreover, a single
point mutation in TM5, G747V, altered the architecture of the common
allosteric site such that 4-nitro-<i>N</i>-(1,3-diphenyl-1<i>H</i>-pyrazol-5-yl)benzamide (VU29) was noncompetitive with
the common allosteric site. Our findings highlight the subtleties
of allosteric modulator binding to mGlu<sub>5</sub> and demonstrate
the utility in incorporating SAR information to strengthen the interpretation
and analyses of docking and mutational data
Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents
Previous
preclinical work has demonstrated the therapeutic potential
of antagonists of the group II metabotropic glutamate receptors (mGlus).
Still, compounds that are selective for the individual group II mGlus
(mGlu<sub>2</sub> and mGlu<sub>3</sub>) have been scarce. There remains
a need for such compounds with the balance of properties suitable
for convenient use in a wide array of rodent behavioral studies. We
describe here the discovery of a selective mGlu<sub>3</sub> NAM <b>106</b> (VU0650786) suitable for in vivo work. Compound <b>106</b> is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-<i>a</i>]pyrazine-4(5<i>H</i>)-one compounds originally
identified as a mGlu<sub>5</sub> positive allosteric modulator (PAM)
chemotype. Its suitability for use in rodent behavioral models has
been established by extensive in vivo PK studies, and the behavioral
experiments presented here with compound <b>106</b> represent
the first examples in which an mGlu<sub>3</sub> NAM has demonstrated
efficacy in models where prior efficacy had previously been noted
with nonselective group II antagonists
Discovery of <i>N</i>‑(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation
Preclinical evidence in support of
the potential utility of mGlu<sub>5</sub> NAMs for the treatment of
a variety of psychiatric and neurodegenerative
disorders is extensive, and multiple such molecules have entered clinical
trials. Despite some promising results from clinical studies, no small
molecule mGlu<sub>5</sub> NAM has yet to reach market. Here we present
the discovery and evaluation of <i>N</i>-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide
(<b>27</b>, VU0424238), a compound selected for clinical evaluation.
Compound <b>27</b> is more than 900-fold selective for mGlu<sub>5</sub> versus the other mGlu receptors, and binding studies established
a <i>K</i><sub>i</sub> value of 4.4 nM at a known allosteric
binding site. Compound <b>27</b> had a clearance of 19.3 and
15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging
studies using a known mGlu<sub>5</sub> PET ligand demonstrated 50%
receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous
dose of 0.06 mg/kg in baboons
Discovery of <i>N</i>‑(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation
Preclinical evidence in support of
the potential utility of mGlu<sub>5</sub> NAMs for the treatment of
a variety of psychiatric and neurodegenerative
disorders is extensive, and multiple such molecules have entered clinical
trials. Despite some promising results from clinical studies, no small
molecule mGlu<sub>5</sub> NAM has yet to reach market. Here we present
the discovery and evaluation of <i>N</i>-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide
(<b>27</b>, VU0424238), a compound selected for clinical evaluation.
Compound <b>27</b> is more than 900-fold selective for mGlu<sub>5</sub> versus the other mGlu receptors, and binding studies established
a <i>K</i><sub>i</sub> value of 4.4 nM at a known allosteric
binding site. Compound <b>27</b> had a clearance of 19.3 and
15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging
studies using a known mGlu<sub>5</sub> PET ligand demonstrated 50%
receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous
dose of 0.06 mg/kg in baboons