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

• Published in: Journal of medicinal chemistry Vol. 60; no. 18; pp. 7658 - 7676
• Main Authors: Mikami, Satoshi, Sasaki, Shigekazu, Asano, Yasutomi, Ujikawa, Osamu, Fukumoto, Shoji, Nakashima, Kosuke, Oki, Hideyuki, Kamiguchi, Naomi, Imada, Haruka, Iwashita, Hiroki, Taniguchi, Takahiko
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.09.2017; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Brain - drug effects; Brain - metabolism; Chemistry, Medicinal; Cognition Disorders - drug therapy; Cognition Disorders - enzymology; Cognition Disorders - metabolism; Cyclic GMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 2 - antagonists & inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 2 - metabolism; Drug Discovery; Humans; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Pharmacology & Pharmacy; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacokinetics; Phosphodiesterase Inhibitors - pharmacology; Pyrimidines - administration & dosage; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Rats; Science & Technology; HIPPOCAMPUS; OBSTRUCTIVE PULMONARY-DISEASE; PERSPECTIVE; MILRINONE; EFFICACY; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; CGMP; SYNAPTIC PLASTICITY; ROFLUMILAST; SELECTIVITY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00709

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 18 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-N-((1R)-1-(4-(trifluoromethoxy)­phenyl)­propyl)­pyrazolo­[1,5-a]­pyrimidine-3-carboxamide (38a), a molecule with the desired balance of preclinical properties. Further characterization by cocrystal structure analysis of 38a bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound 38a 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.