ABSTRACT
Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.
Subject(s)
Azepines/chemistry , Azirines/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Dihydropyridines/chemistry , Phosphodiesterase Inhibitors/chemistry , Pyrazoles/chemistry , Analgesics/chemistry , Analgesics/pharmacokinetics , Analgesics/therapeutic use , Animals , Azepines/pharmacokinetics , Azepines/therapeutic use , Azirines/pharmacokinetics , Azirines/therapeutic use , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Dihydropyridines/pharmacokinetics , Dihydropyridines/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Osteoarthritis/drug therapy , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphodiesterase Inhibitors/therapeutic use , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.
