RESUMO
A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
Assuntos
Benzoxazóis/farmacocinética , Indóis/farmacocinética , Transtornos da Memória/tratamento farmacológico , Agonistas Muscarínicos/farmacocinética , Nootrópicos/farmacocinética , Receptor Muscarínico M1/metabolismo , Animais , Benzoxazóis/química , Benzoxazóis/uso terapêutico , Encéfalo/metabolismo , Indóis/química , Indóis/uso terapêutico , Agonistas Muscarínicos/química , Agonistas Muscarínicos/uso terapêutico , Nootrópicos/química , Nootrópicos/uso terapêutico , Oxindóis , RatosRESUMO
Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Quinolinas/síntese química , Receptores da Neurocinina-3/antagonistas & inibidores , Aminas/metabolismo , Animais , Área Sob a Curva , Encéfalo/metabolismo , Córtex Cerebral/embriologia , Gerbillinae , Masculino , Modelos Químicos , Quinolinas/metabolismo , Quinolinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Assuntos
Quinolinas/farmacologia , Receptores 5-HT1 de Serotonina/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Ligantes , Quinolinas/administração & dosagem , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.
