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 imidazo­[4,5-<i>b</i>]­pyridines 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 imidazo­[4,5-<i>b</i>]­pyridine <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 imidazo­[4,5-<i>b</i>]­pyridines (<b>4</b>, <b>7</b>, <b>12b</b>, <b>24a</b>, and <b>24b</b>) with PDE10A IC₅₀ 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 imidazo­[4,5-<i>b</i>]­pyridines 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 imidazo­[4,5-<i>b</i>]­pyridine <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 imidazo­[4,5-<i>b</i>]­pyridines (<b>4</b>, <b>7</b>, <b>12b</b>, <b>24a</b>, and <b>24b</b>) with PDE10A IC₅₀ 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_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

Human genetic evidence has identified the voltage-gated sodium channel Na_V1.7 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_V1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log <i>D</i>) while maintaining Na_V1.7 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_V1.7 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_V1.7 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_V1.7 inhibitors that demonstrate high levels of selectivity over other Na_V 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_V1.7, which demonstrate nanomolar inhibition of Na_V1.7 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_V1.7-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_V1.7 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_V1.7 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_V1.7 inhibitors that demonstrate high levels of selectivity over other Na_V 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_V1.7, which demonstrate nanomolar inhibition of Na_V1.7 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_V1.7-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