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

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket

Structure–activity relationship investigations conducted at the 5-position of the <i>N</i>-pyridine ring of a series of <i>N</i>-arylsulfonyl-<i>N</i>′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (<b>51</b>) that was a potent disruptor of the glucokinase–glucokinase regulatory protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound <b>51</b> bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound <b>51</b> was potent in both biochemical and cellular assays (IC₅₀ = 0.005 μM and EC₅₀ = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to <i>db/db</i> mice (100 mg/kg, po), compound <b>51</b> demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis

The glucokinase–glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure–activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone <b>93</b>, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 3. Structure–Activity Relationships within the Aryl Carbinol Region of the <i>N</i>‑Arylsulfonamido‑<i>N</i>′‑arylpiperazine Series

We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2<i>S</i>)-4-((6-amino-3-pyridinyl)­sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)­phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (<b>1</b>, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound <b>1</b> bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives <b>24</b> and <b>29</b> possessed excellent potency as well as favorable PK properties. When dosed orally in <i>db</i>/<i>db</i> mice, both compounds significantly lowered fed blood glucose levels (up to 58%)

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

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept

Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide <b>25</b> (AMG-1694). When dosed in ZDF rats, <b>25</b> showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles

In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of <b>1</b> (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (<b>27</b>, AMG-3969). When administered to <i>db</i>/<i>db</i> mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels

Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) Binding: Strategic Use of a N → S (n_N → σ*_S–X) Interaction for Conformational Constraint

The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK–GKRP disrupters are revealed. Diarylmethane­sulfonamide hit <b>6</b> (hGK–hGKRP IC₅₀ = 1.2 μM) was optimized to lead compound <b>32</b> (AMG-0696; hGK–hGKRP IC₅₀ = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (n_N → σ*_S–X) in <b>32</b> was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound <b>32</b> was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = −45%; 100 mg/kg po, 3 h). X-ray analyses of <b>32</b> and several precursors bound to GKRP were also obtained. This novel disrupter of GK–GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design