Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders

Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit <b>18</b> were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA). Combining these structural elements led to the identification of 6-methyl-<i>N</i>-((1<i>R</i>)-1-(4-(trifluoromethoxy)­phenyl)­propyl)­pyrazolo­[1,5-<i>a</i>]­pyrimidine-3-carboxamide (<b>38a</b>), a molecule with the desired balance of preclinical properties. Further characterization by cocrystal structure analysis of <b>38a</b> bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound <b>38a</b> significantly elevated 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brain following oral administration, thus validating this compound as a useful pharmacological tool and an attractive lead for future optimization

Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders

Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit <b>18</b> were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA). Combining these structural elements led to the identification of 6-methyl-<i>N</i>-((1<i>R</i>)-1-(4-(trifluoromethoxy)­phenyl)­propyl)­pyrazolo­[1,5-<i>a</i>]­pyrimidine-3-carboxamide (<b>38a</b>), a molecule with the desired balance of preclinical properties. Further characterization by cocrystal structure analysis of <b>38a</b> bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound <b>38a</b> significantly elevated 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brain following oral administration, thus validating this compound as a useful pharmacological tool and an attractive lead for future optimization

Discovery of Clinical Candidate <i>N</i>‑((1<i>S</i>)‑1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3‑<i>b</i>]pyrazine-4(1<i>H</i>)‑carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders

Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer’s disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo­[1,5-<i>a</i>]­pyrimidine lead compound <b>4b</b>, leading to the discovery of clinical candidate <b>36</b> (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of <b>36</b> was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of <b>36</b> demonstrated significant elevation of 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound <b>36</b> was advanced into human clinical trials