RESUMO
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
Assuntos
Fármacos Anti-HIV/síntese química , Compostos Azabicíclicos/síntese química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Imidazóis/síntese química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Linhagem Celular , Cricetinae , Cicloexanos/farmacologia , Cães , Farmacorresistência Viral , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , HIV-1/isolamento & purificação , Humanos , Imidazóis/química , Imidazóis/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Maraviroc , Modelos Moleculares , Ligação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacologia , TropanosRESUMO
This Letter reports the design and synthesis of several novel series of piperazinyl pyrimidinones as 5-HT(2C) agonists. Several of the compounds presented exhibit good in vitro potency and selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compound 11 was active in in vivo models of stress urinary incontinence.
Assuntos
Pirimidinonas/química , Pirimidinonas/uso terapêutico , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Pirimidinonas/farmacologia , Receptor 5-HT2B de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , Uretra/efeitos dos fármacos , Incontinência Urinária/tratamento farmacológicoRESUMO
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.
Assuntos
Agonistas do Receptor A2 de Adenosina , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Adenosina/análogos & derivados , Adenosina/química , Administração por Inalação , Adolescente , Adulto , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Pulmão/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Fenetilaminas/química , Purinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.
Assuntos
Agonistas do Receptor A2 de Adenosina , Adenosina/análogos & derivados , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Adenosina/farmacocinética , Adenosina/farmacologia , Administração por Inalação , Administração Oral , Aminas/farmacocinética , Aminas/farmacologia , Animais , Cobaias , Humanos , Pulmão/metabolismo , Fenetilaminas/farmacocinética , Fenetilaminas/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
This paper reports the synthesis and biological activity of a novel series of aryl-morpholine dopamine receptor agonists. Several compounds show high levels of functional selectivity for the D3 over the D2 dopamine receptor. Compound 26 has >1000-fold functional selectivity and has been successfully progressed in vivo using an intranasal delivery route.