Design and Discovery of 6‑[(3S,4S)‑4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro‑2H‑pyran-4-yl)-1,5-dihydro‑4H‑pyrazolo[3,4‑d]pyrimidin-4-one (PF-04447943), a Selective Brain Penetrant PDE9A Inhibitor for the Treatment of Cognitive Disorders

• Published in: Journal of medicinal chemistry Vol. 55; no. 21; pp. 9045 - 9054
• Main Authors: Verhoest, Patrick R, Fonseca, Kari R, Hou, Xinjun, Proulx-LaFrance, Caroline, Corman, Michael, Helal, Christopher J, Claffey, Michelle M, Tuttle, Jamison B, Coffman, Karen J, Liu, Shenpinq, Nelson, Frederick, Kleiman, Robin J, Menniti, Frank S, Schmidt, Christopher J, Vanase-Frawley, Michelle, Liras, Spiros
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.11.2012; Amer Chemical Soc
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Amyloid beta-Protein Precursor - genetics; Animals; Brain - metabolism; Catalytic Domain; Chemistry, Medicinal; Cognition Disorders - drug therapy; Crystallography, X-Ray; Cyclic GMP - metabolism; Dogs; Drug Design; Hippocampus - drug effects; Hippocampus - physiology; Humans; Life Sciences & Biomedicine; Long-Term Potentiation - drug effects; Maze Learning - drug effects; Mice; Mice, Transgenic; Microsomes, Liver - metabolism; Models, Molecular; Pharmacology & Pharmacy; Protein Conformation; Pyrazoles - chemical synthesis; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacokinetics; Pyrimidinones - pharmacology; Rats; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Synapses - drug effects; Synapses - physiology; CGMP-SPECIFIC PHOSPHODIESTERASE; RODENTS; MILRINONE; ALIGNMENT; ADME; DRUGS; CNS; CENTRAL-NERVOUS-SYSTEM; SYNAPTIC PLASTICITY; BINDING

6-[(3S,4S)-4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943) is a novel PDE9A inhibitor identified using parallel synthetic chemistry and structure-based drug design (SBDD) and has advanced into clinical trials....