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J Med Chem ; 55(21): 9055-68, 2012 Nov 08.
Article in English | MEDLINE | ID: mdl-23025719

ABSTRACT

Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. 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.


Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Azetidines/chemistry , Blood-Brain Barrier/metabolism , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Pyrimidinones/chemistry , 3',5'-Cyclic-AMP Phosphodiesterases/chemistry , Administration, Oral , Animals , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Crystallography, X-Ray , Cyclic GMP/cerebrospinal fluid , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Cyclopentanes/pharmacokinetics , Databases, Factual , Dogs , Drug Design , Humans , Models, Molecular , Molecular Structure , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity Relationship
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