RESUMO
SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A(2A) receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A(2A) receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 microM at physiological pH.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Química Farmacêutica/métodos , Doença de Parkinson/tratamento farmacológico , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética , Adenosina/química , Administração Oral , Animais , Área Sob a Curva , Modelos Animais de Doenças , Desenho de Fármacos , Concentração de Íons de Hidrogênio , Modelos Químicos , Pirimidinas/química , Ratos , Solubilidade , Triazóis/química , Água/químicaRESUMO
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Assuntos
Disfunção Erétil/tratamento farmacológico , Fosfodiesterase I/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Purinas/síntese química , Purinas/uso terapêutico , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Piperazinas/farmacologia , Purinas/química , Ratos , Citrato de Sildenafila , Relação Estrutura-Atividade , Sulfonas , Vasodilatadores/síntese química , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêuticoRESUMO
We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.
Assuntos
Benzamidas/química , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacocinética , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Acetilcolina/análise , Acetilcolina/biossíntese , Animais , Área Sob a Curva , Benzamidas/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Microdiálise , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Receptores Muscarínicos/metabolismo , Relação Estrutura-AtividadeRESUMO
We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).