Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose–response model

Aims Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose-response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. Methods And Results Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1-3 clinical studies. Dose-response models were developed for bempedoic acid monotherapy and bempedoic acid-statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose-response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose" for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. Conclusion These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses

Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1<i>H</i>)‑one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists

We report the design and synthesis of novel 5,6-diarylated pyridin-2­(1<i>H</i>)-one derivatives as pharmacophoric PDE10A inhibitors. This highly potent molecular scaffold was developed from an inactive diarylpyridine-2-amine derivative <b>3b</b> by extensive and systematic analogue synthesis and SAR analysis. Further optimization of the scaffold resulted in identification of pyridin-2­(1<i>H</i>)-one <b>18b</b> as a lead compound with good potency (IC₅₀ = 1.6 nM) and selectivity (>6000-fold) over other related PDEs but with a poor pharmacokinetic profile. Careful metabolite profiling of <b>18b</b> revealed that poor systemic exposure in rats (<i>C</i>_max = 44 ng/mL; AUC_0–<i>t</i> = 359 ng·h/mL) at 10 mg/kg was due to the formation of <i>O</i>-glucuronide conjugate by phase 2 metabolism. The structure of the glucuronide metabolite was confirmed by retention time and LC–MS/MS fragmentation matching with the synthetic glucuronide <b>26</b>. The problem of low exposure of <b>18b</b> was effectively addressed by its conversion to an acetate prodrug <b>25b</b>, which upon oral dosing resulted in an improved pharmacokinetic profile (<i>C</i>_max = 359 ng.h/mL; AUC_0–<i>t</i> = 2436 ng.h/mL) and a desirable brain to plasma ratio of 1.2. The prodrug <b>25b</b> showed good efficacy in selected rodent models of psychosis