Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies

We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BP_ND) in NHP than our previously reported tracer <b>1</b>, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (<b>2</b>–<b>6</b>) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (<b>2</b>, <b>3</b>) and one keto-benzimidazole (<b>5</b>) exhibited PDE10A target specificity and brain uptake comparable to or better than <b>1</b> in the in vivo LC–MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [¹⁸F]-<b>5</b> produced a significantly improved BP_ND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies

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