ABSTRACT
An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
Subject(s)
Acetic Acid/pharmacology , Cognitive Dysfunction/drug therapy , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Indoles/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Acetic Acid/chemical synthesis , Acetic Acid/chemistry , Animals , Catalytic Domain/drug effects , Cognitive Dysfunction/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Dose-Response Relationship, Drug , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.
