Patrick R Verhoest
Affiliation: Pfizer Global Research and Development
- 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 disorPatrick R Verhoest
Neuroscience Medicinal Chemistry, Pfizer World Wide Research and Development, 700 Main Street, Cambridge, Massachusetts 02139, United States
J Med Chem 55:9045-54. 2012....
- Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophreniaPatrick R Verhoest
Neuroscience, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
J Med Chem 52:5188-96. 2009..This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia...
- Design and discovery of a selective small molecule κ opioid antagonist (2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242)Patrick R Verhoest
Neuroscience Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Groton, Connecticut, USA
J Med Chem 54:5868-77. 2011..This strategy identified 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers...
- Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitorsMichelle M Claffey
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
J Med Chem 55:9055-68. 2012..Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF...
- PF-04859989 as a template for structure-based drug design: identification of new pyrazole series of irreversible KAT II inhibitors with improved lipophilic efficiencyAmy B Dounay
Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA
Bioorg Med Chem Lett 23:1961-6. 2013..53. The X-ray crystal structure of 20 with KAT II demonstrates key features that contribute to this remarkable potency and binding efficiency...
- Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributesTravis T Wager
558 Eastern Point Road, Groton, CT, USA
ACS Chem Neurosci 1:420-34. 2010....
- Design and selection parameters to accelerate the discovery of novel central nervous system positron emission tomography (PET) ligands and their application in the development of a novel phosphodiesterase 2A PET ligandLei Zhang
Neuroscience Medicinal Chemistry, Pfizer Inc, Cambridge, Massachusetts 02139, USA
J Med Chem 56:4568-79. 2013....
- Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivoRobin J Kleiman
SystaMedic Inc, 1084 Shennecossett Drive, Groton, CT 06340, USA
J Pharmacol Exp Ther 341:396-409. 2012....
- Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulatLei Zhang
Neuroscience Medicinal Chemistry, Neuroscience Pharmacokinetics, Dynamics and Metabolism, and Neuroscience Research Unit, Pfizer Inc, Cambridge, Massachusetts 02139, United States
J Med Chem 57:861-77. 2014..However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study. ..
- Identification of a brain penetrant PDE9A inhibitor utilizing prospective design and chemical enablement as a rapid lead optimization strategyPatrick R Verhoest
Neuroscience Chemistry, Pfizer Global Research and Development, Groton, CT 06340, USA
J Med Chem 52:7946-9. 2009..By use of chemical enablement and prospective design, a novel series of selective, brain penetrant PDE9A inhibitors have been identified that are capable of producing in vivo elevations of brain cGMP...
- Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike propertiesTravis T Wager
Neuroscience Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, 558 Eastern Point Road, Groton, Connecticut, USA
ACS Chem Neurosci 1:435-49. 2010..Based on six physicochemical properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compounds with increased probability of success...
- Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic StabilityMartin Pettersson
Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States
J Med Chem 59:5284-96. 2016..Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor. ..
- Central Nervous System Multiparameter Optimization Desirability: Application in Drug DiscoveryTravis T Wager
Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
ACS Chem Neurosci 7:767-75. 2016..Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compounds nominated for clinical development. ..
- Design, synthesis, and pharmacological evaluation of a novel series of pyridopyrazine-1,6-dione γ-secretase modulatorsMartin Pettersson
Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, Massachusetts 02139, United States
J Med Chem 57:1046-62. 2014....
- Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIKQi Wang
Neuroscience and Pain Research Unit, BioTherapeutics Research and Development, Pfizer Inc Cambridge, Massachusetts Q W, S p A, D M R, N J B, M D E Center of Chemistry Innovation and Excellence, Pfizer Inc, Groton, Connecticut M M H Neuroscience Medicinal Chemistry, Pfizer Inc, Cambridge, Massachusetts B L K, P R V and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts L X
J Pharmacol Exp Ther 356:410-23. 2016....
- Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitorJaclyn L Henderson
Worldwide Medicinal Chemistry, Neuroscience Research Unit, and Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R and D, 610 Main Street, Cambridge, Massachusetts 02139, United States
J Med Chem 58:419-32. 2015..This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies. ..
- 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile derivatives as potent and tissue selective androgen receptor modulatorsEugene L Piatnitski Chekler
BioTherapeutics Medicinal Chemistry, Pfizer Global Research and Development, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, United States
J Med Chem 57:2462-71. 2014..This lead compound completed a two week rat toxicology study, and was well tolerated at doses up to 100 mg/kg/day, the highest dose tested, for 14 consecutive days. ..
- Evaluating the differences in cycloalkyl ether metabolism using the design parameter "lipophilic metabolism efficiency" (LipMetE) and a matched molecular pairs analysisAntonia F Stepan
Pfizer Worldwide Research and Development, 700 Main Street, Cambridge, Massachusetts 02139, United States
J Med Chem 56:6985-90. 2013..It is our hope that both the LipMetE design parameter and the results from our pairwise analysis will be useful tools for medicinal chemists. ..
- A general strategy for the synthesis of cyclic N-aryl hydroxamic acids via partial nitro group reductionLaura A McAllister
Neuroscience Chemistry, Pfizer Worldwide R and D, Eastern Point Rd, Groton, Connecticut 06340, USA
J Org Chem 76:3484-97. 2011..In addition, a novel activated trifluoroethyl ester cyclization strategy has been developed as an alternate approach to the most sterically demanding systems in this series...