RESUMO
A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.
Assuntos
Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Ácidos Carboxílicos/farmacocinética , Amidas/química , Animais , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/química , Ácidos Carboxílicos/sangue , Ácidos Carboxílicos/química , Descoberta de Drogas , RatosRESUMO
Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.
Assuntos
Fármacos Anti-HIV/química , Benzoatos/química , Antagonistas dos Receptores CCR5 , Dicetopiperazinas/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Benzoatos/síntese química , Benzoatos/farmacocinética , Dicetopiperazinas/síntese química , Dicetopiperazinas/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Cobaias , Haplorrinos , Humanos , Coelhos , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Dicetopiperazinas/química , Compostos de Espiro/química , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Linhagem Celular Tumoral , Dicetopiperazinas/síntese química , Dicetopiperazinas/farmacocinética , Dicetopiperazinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Proteína do Núcleo p24 do HIV/metabolismo , HIV-1/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Receptores CCR5/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , EstereoisomerismoRESUMO
Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/farmacocinética , Administração Oral , Animais , Fármacos Anti-HIV/química , Disponibilidade Biológica , Células CACO-2 , Humanos , Piperazinas/química , Ratos , Receptores CCR5/metabolismoRESUMO
Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.
Assuntos
Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Piperazinas/farmacocinética , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Proteína do Núcleo p24 do HIV/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/química , Ratos , Receptores CCR5/metabolismoRESUMO
Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from beta-substituted (2R,3R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1alpha to human CCR5, compared with the non-hydroxylated derivatives and the other isomers.
