RESUMEN
A series of 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
Asunto(s)
Fármacos Anti-VIH/química , Antagonistas de los Receptores CCR5 , Compuestos Heterocíclicos/química , Pirrolidinas/química , Administración Oral , Animales , Fármacos Anti-VIH/farmacocinética , Células HeLa , Compuestos Heterocíclicos/farmacocinética , Humanos , Pirrolidinas/farmacocinética , Ratas , Receptores CCR5/metabolismoRESUMEN
Synthesis of analogs containing more rigid bicyclic piperidine replacements for the 4-benzyloxycarbonyl-(ethyl)amino-piperidine moiety of the CCR5 antagonist structure, 1, is described. Although similar binding affinity to the lead was achieved with some analogs they were overall less potent anti-HIV agents suggesting that other features besides CCR5 binding are required for good anti-viral activity.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antagonistas de los Receptores CCR5 , Sulfonas/síntesis química , Fármacos Anti-VIH/farmacología , Butanos/síntesis química , Butanos/farmacología , Relación Dosis-Respuesta a Droga , Concentración 50 Inhibidora , Piperidinas/síntesis química , Piperidinas/farmacología , Relación Estructura-Actividad , Sulfonas/farmacología , Virus/efectos de los fármacosRESUMEN
Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antagonistas de los Receptores CCR5 , VIH-1/efectos de los fármacos , Pirrolidinas/síntesis química , Acetatos/química , Fármacos Anti-VIH/farmacología , Sitios de Unión , División Celular/efectos de los fármacos , Células HeLa , Humanos , Piperidinas/síntesis química , Piperidinas/farmacología , Pirrolidinas/química , Relación Estructura-ActividadRESUMEN
Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These compounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antagonistas de los Receptores CCR5 , Sulfonas/síntesis química , Fármacos Anti-VIH/farmacología , Sitios de Unión , Antígenos CD4/metabolismo , Línea Celular , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Piperidinas/química , Receptores CCR5/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/farmacologíaRESUMEN
Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Piperidinas/farmacocinética , Animales , Fármacos Anti-VIH/química , División Celular/efectos de los fármacos , Células HeLa , Humanos , Estructura Molecular , Piperidinas/química , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Piperidinas/farmacocinética , Acetatos/química , Acetatos/farmacocinética , Administración Oral , Animales , Fármacos Anti-VIH/química , Disponibilidad Biológica , Perros , Células HeLa , Humanos , Macaca mulatta , Estructura Molecular , Monocitos/efectos de los fármacos , Piperidinas/química , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Antagonistas de los Receptores CCR5 , Piperidinas/química , Piperidinas/farmacocinética , Pirazoles/química , Animales , Fármacos Anti-VIH/síntesis química , Disponibilidad Biológica , Perros , Células HeLa , Humanos , Estructura Molecular , Monocitos/efectos de los fármacos , Piperidinas/síntesis química , Pirazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , Propionatos/farmacología , Pirrolidinas/farmacología , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Propionatos/farmacocinética , Pirrolidinas/farmacocinéticaRESUMEN
Extensive screening of compound libraries was undertaken to identify compounds with high affinity for the rat NK(1) receptor based on inhibition of [(125)I]-substance P binding. RP67580, SR140333, NKP-608 and GR205171 were selected as compounds of interest, with cloned rat NK(1) receptor binding K(i) values of 0.15-1.9 nM. Despite their high binding affinity, NKP-608 and GR205171 exhibited only a moderate functional antagonism of substance P-induced inositol-1-phosphate accumulation and acidification rate at 1 microM using cloned or native rat NK(1) receptors in vitro. The ability of the compounds to penetrate the CNS was determined by inhibition of NK(1) agonist-induced behaviours in gerbils and rats. GR205171 and NKP-608 potently inhibited GR73632-induced foot drumming in gerbils (ID(50) 0.04 and 0.2 mg/kg i.v., respectively). In contrast, RP67580 and SR140333 were poorly brain penetrant in gerbils (no inhibition at 10 mg/kg i.v.) and were not examined further in vivo. In rats, only high doses of GR205171 (10 or 30 mg/kg s.c.) inhibited NK(1) agonist-induced sniffing and hypertension, whilst NKP-608 (1 or 10 mg/kg i.p.) was without effect. GR205171 (3-30 mg/kg s.c.) caused only partial inhibition of separation-induced vocalisations in rat pups, a response that is known to be NK(1) receptor mediated in other species. These observations demonstrate the shortcomings of currently available NK(1) receptor antagonists for rat psychopharmacology assays.
Asunto(s)
Indoles/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/farmacología , Quinolinas/farmacología , Quinuclidinas/farmacología , Tetrazoles/farmacología , Animales , Células CHO , Cricetinae , Relación Dosis-Respuesta a Droga , Femenino , Gerbillinae , Humanos , Indoles/metabolismo , Isoindoles , Masculino , Piperidinas/metabolismo , Quinolinas/metabolismo , Quinuclidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-1/metabolismo , Tetrazoles/metabolismo , Células Tumorales CultivadasRESUMEN
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.
Asunto(s)
Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Piperidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Células CHO , Quimiocina CCL4 , Cricetinae , Semivida , Células HeLa , Humanos , Enlace de Hidrógeno , Proteínas Inflamatorias de Macrófagos/metabolismo , Piperidinas/farmacocinética , Pirrolidinas/farmacocinética , RatasRESUMEN
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antagonistas de los Receptores CCR5 , Pirrolidinas/farmacocinética , Animales , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Perros , Semivida , Humanos , Leucocitos Mononucleares , Macaca mulatta , Tasa de Depuración Metabólica , Piperidinas/química , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Incorporation of acidic functional groups into a lead CCR5 antagonist identified from a targeted combinatorial library resulted in compounds with enhanced anti-HIV-1 activity and attenuated L-type calcium channel affinity.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , VIH-1/efectos de los fármacos , Animales , Fármacos Anti-VIH/farmacocinética , Células CHO , Canales de Calcio Tipo L/efectos de los fármacos , Fenómenos Químicos , Química Física , Quimiocina CCL4 , Cricetinae , Semivida , Células HeLa , Humanos , Proteínas Inflamatorias de Macrófagos/antagonistas & inhibidores , Ratas , Receptores CCR5/química , Relación Estructura-ActividadRESUMEN
A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , VIH-1/efectos de los fármacos , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Fármacos Anti-VIH/farmacocinética , Células CHO , Permeabilidad de la Membrana Celular , Fenómenos Químicos , Química Física , Quimiocina CCL4 , Cricetinae , Células HeLa , Humanos , Indicadores y Reactivos , Proteínas Inflamatorias de Macrófagos/antagonistas & inhibidores , Pirrolidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A series of CCR5 antagonists containing bicyclic isoxazolidines was generated through a nitrone mediated cycloaddition with olefins bearing the preferred pharmacophores previously described. Potent antagonists (3 and 16) were generated with enhanced affinity for the CCR5 receptor while maintaining antiviral activity against HIV.