RESUMO
Investigations of the structure-activity relationships of 1,3,4-trisubstituted pyrrolidine human CCR5 receptor antagonists afforded orally bioavailable compounds with the ability to inhibit HIV replication in vitro.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV/efeitos dos fármacos , Pirrolidinas/farmacologia , Administração Oral , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Células CHO , Cricetinae , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
A series of 1,3,4-trisubstituted pyrrolidines was discovered to have the ability to displace [(125)I]-MIP-1alpha from the CCR5 receptor expressed on Chinese hamster ovary (CHO) cell membranes. CCR5 activity was found to be dependent on the regiochemistry and the absolute stereochemistry of the pyrrolidine.
Assuntos
Antagonistas dos Receptores CCR5 , Pirrolidinas/farmacologia , Animais , Ligação Competitiva , Células CHO , Quimiocina CCL4 , Cricetinae , Radioisótopos do Iodo , Proteínas Inflamatórias de Macrófagos/química , Proteínas Inflamatórias de Macrófagos/farmacologia , Conformação Molecular , Pirrolidinas/química , Receptores CCR5/genética , TransfecçãoRESUMO
Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Células CHO , Quimiocina CCL4 , Técnicas de Química Combinatória , Cricetinae , Humanos , Concentração Inibidora 50 , Proteínas Inflamatórias de Macrófagos/metabolismo , Piperidinas/síntese química , Piperidinas/química , Piperidinas/metabolismo , Ligação Proteica , Receptores CCR5/genética , Receptores CCR5/metabolismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.
