A5073669283- Phosphodiesterase function and regulation
- Cholinesterase and Neurodegenerative Diseases
- Chemical synthesis and alkaloids
- Receptor Mechanisms and Signaling
- Synthesis and Catalytic Reactions
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Renin-Angiotensin System Studies
- Asymmetric Synthesis and Catalysis
- Neuropeptides and Animal Physiology
- Cyclopropane Reaction Mechanisms
- RNA modifications and cancer
- Offshore Engineering and Technologies
- Neuroscience and Neuropharmacology Research
- Pharmacological Effects and Toxicity Studies
- Chemical Synthesis and Analysis
- Bipolar Disorder and Treatment
- Pharmacological Receptor Mechanisms and Effects
- PI3K/AKT/mTOR signaling in cancer
- Chronic Lymphocytic Leukemia Research
- Biochemical and Molecular Research
- Oil Spill Detection and Mitigation
- Neurotransmitter Receptor Influence on Behavior
- Peroxisome Proliferator-Activated Receptors
- Phenothiazines and Benzothiazines Synthesis and Activities
Pfizer (United States)
2011-2023
Alaska Department of Environmental Conservation
1999
Ohio University
1996
To accelerate the discovery of novel small molecule central nervous system (CNS) positron emission tomography (PET) ligands, we aimed to define a property space that would facilitate ligand design and prioritization, thereby providing higher probability success for PET development. Toward this end, built database consisting 62 ligands have successfully reached clinic 15 radioligands failed in late-stage development as negative controls. A systematic analysis these identified set preferred...
ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTCurrent Landscape of Phosphodiesterase 10A (PDE10A) InhibitionThomas A. Chappie*, Christopher J. Helal, and Xinjun HouView Author Information Neuroscience Medicinal Chemistry, Pfizer, Inc., 700 Main Street, Cambridge, MA 02139, United States*Phone: 617-395-0712. E-mail:[email protected]Cite this: Med. Chem. 2012, 55, 17, 7299–7331Publication Date (Web):July 26, 2012Publication History Received12 April 2012Published online14 August inissue 13...
A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point additional modeling, X-ray, synthetic efforts toward increasing inhibitory potency selectivity versus PDE3A/B. These culminated in discovery 29, potent selective brain penetrable inhibitor PDE10A.
Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions ADME properties two chemotypes. Virtual libraries were docked scored for potential ability, followed visual inspection to prioritize analogs parallel directed synthesis. The process yielded highly potent selective compounds such as 16. New X-ray cocrystal structures enabled rational substituents that...
As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand enable target occupancy measurement vivo. Through systematic and cost-effective PET discovery process, involving expression level (Bmax) biodistribution determination, PET-specific structure-activity relationship (SAR) effort, specific binding assessment using LC-MS/MS "cold tracer"...
Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity preclinical models of cognition. To more fully explore the biology PDE2A inhibition, we sought identify potent with improved brain penetration as compared current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted a highly potent, selective, penetrant compound 71 (PF-05085727) that...
CD33/Siglec 3 is a myeloid lineage cell surface receptor that known to regulate microglia activity. Multiple genome-wide association studies (GWAS) have identified genetic variants in the CD33 gene convey protection from late-onset Alzheimer's disease. Furthermore, mechanistic into GWAS-linked suggest disease attributed alternative splicing of exon 2 pre-mRNA. Using phenomimetic screen, series compounds were found enhance exclusion 2, acting as chemomimetic variants. Additional confirmed...
Analogues substituted with various amines at the 6-position of pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors PDK1 potential anticancer agents. An early lead 2-pyridine-3-ylethylamine substituent showed moderate potency selectivity. Structure-based drug design led to improved selectivity against PI3Kα through a combination cyclizing ethylene spacer into saturated, five-membered substituting...
We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors PDE1. Inhibitor ( S)-3 readily attains free plasma concentrations above PDE1 IC50 values has restricted brain access. The racemic compound 3 inhibits >75% PDE hydrolytic activity in soluble samples human myocardium, consistent with heightened this tissue. These compounds represent promising new tools to probe value inhibition treatment cardiovascular disease.
Computational modeling was used to direct the synthesis of analogs previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core yield compounds significantly enhanced potency. The analog PF-05180999 (30) subsequently identified as a preclinical candidate targeting cognitive impairment associated schizophrenia. Compound 30 demonstrated potent binding PDE2A in brain tissue, dose responsive mouse cGMP increases, and reversal N-methyl-d-aspartate (NMDA)...
Phosphodiesterases (PDEs) regulate the levels of second messengers cAMP and cGMP are important drug targets. PDE10A is highly enriched in medium spiny neurons striatum an attractive target for treatment basal ganglia diseases like schizophrenia, Parkinson's disease, or Huntington's disease. Here we describe design, synthesis, application a variety chemical biology probes, based on first clinically tested inhibitor MP-10, which were used to characterize chemoproteomic profile clinical...
Dopamine receptor antagonism is a compelling molecular target for the treatment of range psychiatric disorders, including substance use disorders. From our corporate compound file, we identified structurally unique D3 (D3R) antagonist scaffold, 1. Through hybrid approach, merged key pharmacophore elements from 1 and agonist 2 to yield novel D3R/D2R PF-4363467 (3). Compound 3 was designed possess CNS drug-like properties as defined by its MPO desirability score (≥4/6). In addition good...
Phosphodiesterase-4 (PDE4), which metabolizes the second messenger cyclic adenosine monophosphate (cAMP), has 4 isozymes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B PDE4D have highest expression in brain may play a role pathophysiology treatment of depression dementia. This study evaluated properties newly developed PDE4B-selective radioligand
We report the diastereoselective and chromatography-free syntheses of four 2-phenyl-6-alkyl-3-aminopiperidines. Ring construction was accomplished through a nitro-Mannich reaction linking nitroketone phenylmethanimine, followed by ring-closure condensation. Relative stereocontrol achieved between C-2 C-3 kinetic protonation nitronate or equilibration nitro group under thermodynamic control. Stereocontrol at C-6 utilizing variety imine reduction methods. The C-2/C-6-cis stereochemistry...
Pyridoazepines are privileged structures in the search for novel drug candidates. We present synthesis of a versatile pyridoazepine scaffold employing precedented rhodium(II)-catalyzed ring expansion and subsequent double-condensation-cyclization with nitroacetamide. The reactions applied several potentially hazardous reagents intermediates, including p-toluenesulfonyl azide nitroacetamide, latter which was determined to be explosive shock-sensitive. Reactions employed were derisked...