RESUMO
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.
Assuntos
Azepinas/química , Azirinas/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Di-Hidropiridinas/química , Inibidores de Fosfodiesterase/química , Pirazóis/química , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Azepinas/farmacocinética , Azepinas/uso terapêutico , Azirinas/farmacocinética , Azirinas/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Di-Hidropiridinas/farmacocinética , Di-Hidropiridinas/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Osteoartrite/tratamento farmacológico , Inibidores da Fosfodiesterase 4/química , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
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.
