RESUMEN
We report the discovery of chroman 28, a potent and selective antagonist of human, nonhuman primate, rat, and rabbit bradykinin B1 receptors (0.4-17 nM). At 90 mg/kg s.c., 28 decreased plasma extravasation in two rodent models of inflammation. A novel method to calculate entropy is introduced and ascribed approximately 30% of the gained affinity between "flexible" 4 (Ki = 132 nM) and "rigid" 28 (Ki = 0.77 nM) to decreased conformational entropy.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Cromanos/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Células CHO , Permeabilidad Capilar/efectos de los fármacos , Chlorocebus aethiops , Cromanos/farmacocinética , Cromanos/farmacología , Cricetinae , Cricetulus , Cristalografía por Rayos X , Entropía , Humanos , Técnicas In Vitro , Modelos Moleculares , Conformación Molecular , Pleuresia/tratamiento farmacológico , Conejos , Ratas , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.
Asunto(s)
Diseño Asistido por Computadora , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/antagonistas & inhibidores , Adenosina Monofosfato/metabolismo , Sitio Alostérico , Glucógeno Fosforilasa/química , Glucógeno Fosforilasa/metabolismo , Glucógeno Fosforilasa de Forma Hepática/antagonistas & inhibidores , Glucógeno Fosforilasa de Forma Hepática/química , Glucógeno Fosforilasa de Forma Hepática/metabolismo , Glucógeno Fosforilasa de Forma Muscular/antagonistas & inhibidores , Glucógeno Fosforilasa de Forma Muscular/química , Glucógeno Fosforilasa de Forma Muscular/metabolismo , Humanos , Técnicas In Vitro , Plomo/química , Plomo/farmacología , Modelos Químicos , Estructura Molecular , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , TermodinámicaRESUMEN
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
A new class of diacid analogues that binds at the AMP site not only are very potent but have approximately 10-fold selectivity in liver versus muscle glycogen phosphorylase (GP) in the in vitro assay. The synthesis, structure, and in vitro and in vivo biological evaluation of these liver selective glycogen phosphorylase inhibitors are discussed.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/antagonistas & inhibidores , Naftoles/síntesis química , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión , Glucógeno Fosforilasa/química , Cinética , Hígado/enzimología , Ratones , Modelos Moleculares , Conformación Molecular , Naftoles/farmacología , Conformación Proteica , Ratas , Relación Estructura-ActividadRESUMEN
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
A novel class of small molecule human granzyme B inhibitors is reported. Compound 20 has a K(i) of 7 nM against human granzyme B and blocks CTL mediated apoptosis with an IC(50) of 3 micromolar.
Asunto(s)
Apoptosis/efectos de los fármacos , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Diseño de Fármacos , Granzimas , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.