ABSTRACT
In Alzheimer disease (AD), the double-strand RNA-dependent kinase protein kinase R (PKR )/EIF2AK2 is activated in brain with increased phosphorylation of its substrate eukaryotic initiation factor 2α (eIF2α). AD risk-promoting factors, such as ApoE4 allele or the accumulation of neurotoxic amyloid-ß oligomers (AßOs), have been associated with activation of PKR-dependent signaling. Here, we report the discovery of a novel potent and selective PKR inhibitor (SAR439883) and demonstrate its neuroprotective pharmacological activity in AD experimental models. In ApoE4 human replacement male mice, 1-week oral treatment with SAR439883 rescued short-term memory impairment in the spatial object recognition test and dose-dependently reduced learning and memory deficits in the Barnes maze test. Moreover, in AßO-injected male mice, a 2-week administration of SAR439883 in diet dose-dependently ameliorated the AßO-induced cognitive impairment in both Y-maze and Morris Water Maze, prevented loss of synaptic proteins, and reduced levels of the proinflammatory cytokine interleukin-1ß In both mouse models, these effects were associated with a dose-dependent inhibition of brain PKR activity as measured by both PKR occupancy and partial lowering of peIF2α levels. Our results provide evidence that selective pharmacological inhibition of PKR by a small selective molecule can rescue memory deficits and prevent neurodegeneration in animal models of AD-like pathology, suggesting that inhibition of PKR is a potential therapeutic approach for AD. SIGNIFICANCE STATEMENT: This study reports the identification of a new small molecule potent and selective protein kinase R (PKR) inhibitor that can prevent cognitive deficits and neurodegeneration in Alzheimer disease (AD) experimental models, including a mouse model expressing the most prevalent AD genetic risk factor ApoE4. With high potency and selectivity, this PKR inhibitor represents a unique tool for investigating the physiological role of PKR and a starting point for developing new drug candidates for AD.
Subject(s)
Alzheimer Disease , Cognition Disorders , Maze Learning , Memory DisordersABSTRACT
The development of a copper-catalyzed cross-coupling between primary and secondary (pseudo)halides and bicyclopentyl Grignard reagents is reported. Highly strained bicyclopentanes can be cross-coupled with a large panel of primary alkyl mesylates and secondary alkyl iodides. The catalytic system is simple and cheap, and the reaction is general and chemoselective.
ABSTRACT
A cobalt-catalyzed cross-coupling between alkyl iodides and cyclopropyl, cyclobutyl, and alkenyl Grignard reagents is disclosed. The reaction allows the introduction of strained rings on a large panel of primary and secondary alkyl iodides. The catalytic system is simple and nonexpensive, and the reaction is general, chemoselective, and diastereoconvergent. The alkene resulting from the cross-coupling can be transformed to substituted cyclopropanes using a Simmons-Smith reaction. The formation of radical intermediates during the coupling is hypothesized.
ABSTRACT
The synthesis and SAR studies of a series of structurally novel small molecule inhibitors of PDE7 are discussed. The best compounds from the series displayed low nanomolar inhibitory activity and are selective versus PDE4.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclic Nucleotide Phosphodiesterases, Type 7 , Humans , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemistry , Structure-Activity Relationship , Thiadiazoles/chemistryABSTRACT
The synthesis and optimization of pharmacokinetic parameters of structurally novel small PDE7 inhibitors is discussed.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacokinetics , Thiadiazoles/pharmacokinetics , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Administration, Oral , Animals , Biological Availability , Cyclic Nucleotide Phosphodiesterases, Type 7 , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistryABSTRACT
The synthesis and SAR studies of spiroquinazolinones as novel PDE7 inhibitors are discussed. The best compounds from the series displayed nanomolar inhibitory affinity and were selective versus other PDE isoenzymes.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Spiro Compounds/chemical synthesis , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Cell Line , Cyclic Nucleotide Phosphodiesterases, Type 7 , Drug Evaluation, Preclinical , Humans , Isoenzymes/metabolism , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Solubility , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
The optimization of 5,8-disubstituted spirocyclohexane-quinazolinones into potent, selective, soluble PDE7 inhibitors with acceptable in vivo pharmacokinetic parameters is presented.