ABSTRACT
PDE8B is a cAMP-specific isoform of the broader class of phosphodiesterases (PDEs). As no selective PDE8B inhibitors had been reported, a high throughput screen was run with the goal of identifying selective tools for exploring the potential therapeutic utility of PDE8B inhibition. Of the numerous hits, one was particularly attractive since it was amenable to rapid deconstruction leading to inhibitors with very high ligand efficiency (LE) and lipophilic ligand efficiency (LLE). These triazolopyrimidines were optimized for potency, selectivity and ADME properties ultimately leading to compound 42. This compound was highly potent and selective with good bioavailability and advanced into pre-clinical development.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Diabetes Mellitus/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Animals , Cells, Cultured , Diabetes Mellitus/drug therapy , Drug Discovery , Enzyme Inhibitors/metabolism , High-Throughput Screening Assays , Humans , Insulin/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Ligands , Microsomes, Liver/metabolism , Protein Binding , Pyrimidines/metabolism , Rats , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/metabolism , Triazoles/pharmacologyABSTRACT
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
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.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/chemistry , Hypoglycemia/drug therapy , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemical synthesis , Phosphodiesterase Inhibitors/chemical synthesis , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Administration, Oral , Catalytic Domain , Crystallography, X-Ray , Cyclic GMP/metabolism , Diabetes Mellitus/drug therapy , Drug Design , Humans , Hypoglycemic Agents/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Permeability , Phosphodiesterase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Using a combination of parallel and directed synthesis, the discovery of a highly potent and selective series of adenosine A3 agonists was achieved. High aqueous solubility, required for the intended parenteral route of administration, was achieved by the presence of one or two basic amine functional groups.
Subject(s)
Adenosine A3 Receptor Agonists , Adenosine/chemical synthesis , Adenosine/pharmacology , Adenosine/analogs & derivatives , Humans , Molecular Conformation , Solubility , Stereoisomerism , Structure-Activity Relationship , Water/chemistryABSTRACT
Selective adenosine A(3) agonists have potential utility for the prevention of perioperative myocardial ischemic injury. Herein, we report on the discovery and synthesis of compound 7. This amino nucleoside agonist possesses unprecedented levels of selectivity for the human adenosine A(3) receptor.
