6 research outputs found
Discovery of Novel Imidazo[4,5‑<i>b</i>]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)
We report the discovery of novel
imidazoÂ[4,5-<i>b</i>]Âpyridines as potent and selective inhibitors
of PDE10A. The investigation
began with our recently disclosed ketobenzimidazole <b>1</b>, which exhibited single digit nanomolar PDE10A activity but poor
oral bioavailability. To improve oral bioavailability, we turned to
novel scaffold imidazoÂ[4,5-<i>b</i>]Âpyridine <b>2</b>, which not only retained nanomolar PDE10A activity but was also
devoid of the morpholine metabolic liability. Structure–activity
relationship studies were conducted systematically to examine how
various regions of the molecule impacted potency. X-ray cocrystal
structures of compounds <b>7</b> and <b>24</b> in human
PDE10A helped to elucidate the key bonding interactions. Five of the
most potent and structurally diverse imidazoÂ[4,5-<i>b</i>]Âpyridines (<b>4</b>, <b>7</b>, <b>12b</b>, <b>24a</b>, and <b>24b</b>) with PDE10A IC<sub>50</sub> values
ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies.
Four of them (<b>4</b>, <b>12b</b>, <b>24a</b>,
and <b>24b</b>) achieved 55–74% RO at 10 mg/kg po
Discovery of Novel Imidazo[4,5‑<i>b</i>]pyridines as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)
We report the discovery of novel
imidazoÂ[4,5-<i>b</i>]Âpyridines as potent and selective inhibitors
of PDE10A. The investigation
began with our recently disclosed ketobenzimidazole <b>1</b>, which exhibited single digit nanomolar PDE10A activity but poor
oral bioavailability. To improve oral bioavailability, we turned to
novel scaffold imidazoÂ[4,5-<i>b</i>]Âpyridine <b>2</b>, which not only retained nanomolar PDE10A activity but was also
devoid of the morpholine metabolic liability. Structure–activity
relationship studies were conducted systematically to examine how
various regions of the molecule impacted potency. X-ray cocrystal
structures of compounds <b>7</b> and <b>24</b> in human
PDE10A helped to elucidate the key bonding interactions. Five of the
most potent and structurally diverse imidazoÂ[4,5-<i>b</i>]Âpyridines (<b>4</b>, <b>7</b>, <b>12b</b>, <b>24a</b>, and <b>24b</b>) with PDE10A IC<sub>50</sub> values
ranging from 0.8 to 6.7 nM were advanced into receptor occupancy studies.
Four of them (<b>4</b>, <b>12b</b>, <b>24a</b>,
and <b>24b</b>) achieved 55–74% RO at 10 mg/kg po
Discovery of Clinical Candidate 1‑(4-(3-(4-(1<i>H</i>‑Benzo[<i>d</i>]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), A Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)
We report the identification of a
PDE10A clinical candidate by
optimizing potency and in vivo efficacy of promising keto-benzimidazole
leads <b>1</b> and <b>2</b>. Significant increase in biochemical
potency was observed when the saturated rings on morpholine <b>1</b> and <i>N</i>-acetyl piperazine <b>2</b> were
changed by a single atom to tetrahydropyran <b>3</b> and <i>N</i>-acetyl piperidine <b>5</b>. A second single atom
modification from pyrazines <b>3</b> and <b>5</b> to pyridines <b>4</b> and <b>6</b> improved the inhibitory activity of <b>4</b> but not <b>6</b>. In the in vivo LC–MS/MS target
occupancy (TO) study at 10 mg/kg, <b>3</b>, <b>5</b>,
and <b>6</b> achieved 86–91% occupancy of PDE10A in the
brain. Furthermore, both CNS TO and efficacy in PCP-LMA behavioral
model were observed in a dose dependent manner. With superior in vivo
TO, in vivo efficacy and in vivo PK profiles in multiple preclinical
species, compound <b>5</b> (AMG 579) was advanced as our PDE10A
clinical candidate
Sulfonamides as Selective Na<sub>V</sub>1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement
Human
genetic evidence has identified the voltage-gated sodium
channel Na<sub>V</sub>1.7 as an attractive target for the treatment
of pain. We initially identified naphthalene sulfonamide <b>3</b> as a potent and selective inhibitor of Na<sub>V</sub>1.7. Optimization
to reduce biliary clearance by balancing hydrophilicity and hydrophobicity
(Log <i>D</i>) while maintaining Na<sub>V</sub>1.7 potency
led to the identification of quinazoline <b>16</b> (AM-2099).
Compound <b>16</b> demonstrated a favorable pharmacokinetic
profile in rat and dog and demonstrated dose-dependent reduction of
histamine-induced scratching bouts in a mouse behavioral model following
oral dosing
Sulfonamides as Selective Na<sub>V</sub>1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity
Because of its strong genetic validation,
Na<sub>V</sub>1.7 has
attracted significant interest as a target for the treatment of pain.
We have previously reported on a number of structurally distinct bicyclic
heteroarylsulfonamides as Na<sub>V</sub>1.7 inhibitors that demonstrate
high levels of selectivity over other Na<sub>V</sub> isoforms. Herein,
we report the discovery and optimization of a series of atropisomeric
quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors
and their preparation. WO 2014201206, 2014] of Na<sub>V</sub>1.7, which demonstrate nanomolar inhibition of
Na<sub>V</sub>1.7 and exhibit high levels of selectivity over other
sodium channel isoforms. After optimization of metabolic and pharmacokinetic
properties, including PXR activation, CYP2C9 inhibition, and CYP3A4
TDI, several compounds were advanced into in vivo target engagement
and efficacy models. When tested in mice, compound <b>39</b> (AM-0466) demonstrated robust pharmacodynamic activity in a Na<sub>V</sub>1.7-dependent model of histamine-induced pruritus (itch) and
additionally in a capsaicin-induced nociception model of pain without
any confounding effect in open-field activity
Sulfonamides as Selective Na<sub>V</sub>1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity
Because of its strong genetic validation,
Na<sub>V</sub>1.7 has
attracted significant interest as a target for the treatment of pain.
We have previously reported on a number of structurally distinct bicyclic
heteroarylsulfonamides as Na<sub>V</sub>1.7 inhibitors that demonstrate
high levels of selectivity over other Na<sub>V</sub> isoforms. Herein,
we report the discovery and optimization of a series of atropisomeric
quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors
and their preparation. WO 2014201206, 2014] of Na<sub>V</sub>1.7, which demonstrate nanomolar inhibition of
Na<sub>V</sub>1.7 and exhibit high levels of selectivity over other
sodium channel isoforms. After optimization of metabolic and pharmacokinetic
properties, including PXR activation, CYP2C9 inhibition, and CYP3A4
TDI, several compounds were advanced into in vivo target engagement
and efficacy models. When tested in mice, compound <b>39</b> (AM-0466) demonstrated robust pharmacodynamic activity in a Na<sub>V</sub>1.7-dependent model of histamine-induced pruritus (itch) and
additionally in a capsaicin-induced nociception model of pain without
any confounding effect in open-field activity