RESUMO
We describe the design, synthesis and profiling of a novel series of PDE5 inhibitors. We take advantage of an alternate projection into the solvent region to identify compounds with excellent potency, selectivity and pharmacokinetic profiles.
Assuntos
Inibidores da Fosfodiesterase 5/farmacologia , Pirazinas/farmacologia , Cristalografia por Raios X , Concentração Inibidora 50 , Modelos Moleculares , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacocinética , Pirazinas/química , Pirazinas/farmacocinética , Solventes/químicaRESUMO
Human ß-nerve growth factor (ß-NGF) and its associated receptor, human tropomyosin receptor kinase A (hTrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located hTrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective hTrkA allosteric inhibitor, 1. 1 was shown to be active against the full length hTrkA, showing preferential binding for the inactive kinase, and was confirmed through the X-ray of hTrkA···1 bound complex. 1 was also found to inhibit ß-NGF induced neurite outgrowth in rat PC12 cells. Daily oral administration of 1 improved the joint compression threshold of rats injected intra-articularly with monoiodoacetate over a 14-day period. The efficacy of 1 in a relevant chronic pain model of osteoarthritis coupled with in vitro confirmation of target mediation makes allosteric hTrkA inhibitors potential candidates for modulating pain.
RESUMO
We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
Assuntos
Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/química , Pirazinas/química , Piridinas/química , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Cães , Descoberta de Drogas , Humanos , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Pirazinas/síntese química , Pirazinas/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-AtividadeRESUMO
Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.
Assuntos
Aminopiridinas/síntese química , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/síntese química , Pirazinas/síntese química , Administração Oral , Aminopiridinas/farmacologia , Animais , Química Farmacêutica/métodos , GMP Cíclico/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Hipertensão/tratamento farmacológico , Microssomos/efeitos dos fármacos , Modelos Químicos , Inibidores de Fosfodiesterase/farmacologia , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Inibidores da Fosfodiesterase 5 , Pirazinas/síntese química , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Domínio Catalítico , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/química , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Estrutura Terciária de Proteína , Pirazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.