ABSTRACT
The first highly potent and selective PDE8 inhibitors are disclosed. The initial tetrahydroisoquinoline hit was transformed into a nipecotic amide series in order to address a reactive metabolite issue. Reduction of lipophilicity to address metabolic liabilities uncovered an interesting diastereomer-dependent trend in turnover by human microsomes.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Enzyme Inhibitors/pharmacology , Microsomes/drug effects , Nipecotic Acids/chemistry , Amides/chemistry , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Ligands , Models, Molecular , Molecular StructureABSTRACT
Novel hygromycin A derivatives bearing a variety of functionalized aminocyclitol moieties have been synthesized in an effort to increase the antibacterial activity and drug-like properties of this class of agents. A systematic study of the effect of alkylation and removal of the hydroxyls of the aminocyclitol directed us to a series of alkylated aminocyclitol derivatives with improved gram-positive activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cinnamates/chemical synthesis , Cinnamates/pharmacology , Hygromycin B/analogs & derivatives , Hygromycin B/chemical synthesis , Hygromycin B/pharmacology , Microbial Sensitivity TestsABSTRACT
Starting from a non-selective pyrazolo-pyrimidone lead, the sequential use of parallel medicinal chemistry and directed synthesis led to the discovery of potent, highly selective, and orally bioavailable PDE9 inhibitors. The availability of these tools allowed for a thorough evaluation of the therapeutic potential of PDE9 inhibition.
