RESUMO
The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
Assuntos
Benzamidas/síntese química , Óxidos N-Cíclicos/síntese química , Disfunção Erétil/tratamento farmacológico , Receptores de Dopamina D4/agonistas , Potenciais de Ação , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Linhagem Celular , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacologia , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/fisiologia , Haplorrinos , Humanos , Técnicas In Vitro , Masculino , Técnicas de Patch-Clamp , Ramos Subendocárdicos/efeitos dos fármacos , Ramos Subendocárdicos/fisiologia , Ratos , Relação Estrutura-AtividadeRESUMO
A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 micromol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D4 selective agonism in this series of analogues.
