RESUMEN
Previous work has suggested that activation of mGlu5 receptor augments NMDA receptor function and thereby may constitute a rational approach addressing glutamate hypofunction in schizophrenia and a target for novel antipsychotic drug development. Here, we report the in vitro activity, in vivo efficacy and safety profile of 5PAM523 (4-Fluorophenyl){(2R,5S)-5-[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]-2-methylpiperidin-1-yl}methanone), a structurally novel positive allosteric modulator selective of mGlu5. In cells expressing human mGlu5 receptor, 5PAM523 potentiated threshold responses to glutamate in fluorometric calcium assays, but does not have any intrinsic agonist activity. 5PAM523 acts as an allosteric modulator as suggested by the binding studies showing that 5PAM523 did not displace the binding of the orthosteric ligand quisqualic acid, but did partially compete with the negative allosteric modulator, MPyEP. In vivo, 5PAM523 reversed amphetamine-induced locomotor activity in rats. Therefore, both the in vitro and in vivo data demonstrate that 5PAM523 acts as a selective mGlu5 PAM and exhibits anti-psychotic like activity. To study the potential for adverse effects and particularly neurotoxicity, brain histopathological exams were performed in rats treated for 4 days with 5PAM523 or vehicle. The brain exam revealed moderate to severe neuronal necrosis in the rats treated with the doses of 30 and 50 mg/kg, particularly in the auditory cortex and hippocampus. To investigate whether this neurotoxicity is mechanism specific to 5PAM523, similar safety studies were carried out with three other structurally distinct selective mGlu5 PAMs. Results revealed a comparable pattern of neuronal cell death. Finally, 5PAM523 was tested in mGlu5 knock-out (KO) and wild type (WT) mice. mGlu5 WT mice treated with 5PAM523 for 4 days at 100 mg/kg presented significant neuronal death in the auditory cortex and hippocampus. Conversely, mGlu5 KO mice did not show any neuronal loss by histopathology, suggesting that enhancement of mGlu5 function is responsible for the toxicity of 5PAM523. This study reveals for the first time that augmentation of mGlu5 function with selective allosteric modulators results in neurotoxicity.
Asunto(s)
Antipsicóticos/toxicidad , Benzamidas/toxicidad , Encéfalo/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Fármacos actuantes sobre Aminoácidos Excitadores/toxicidad , Oxadiazoles/toxicidad , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica , Animales , Antipsicóticos/química , Antipsicóticos/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Encéfalo/patología , Encéfalo/fisiopatología , Células CHO , Muerte Celular/fisiología , Células Cultivadas , Cricetulus , Fármacos actuantes sobre Aminoácidos Excitadores/química , Fármacos actuantes sobre Aminoácidos Excitadores/farmacocinética , Femenino , Humanos , Masculino , Ratones de la Cepa 129 , Ratones Noqueados , Necrosis/patología , Necrosis/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/fisiología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/fisiopatología , Oxadiazoles/química , Oxadiazoles/farmacocinética , Ratas Sprague-Dawley , Ratas Wistar , Receptor del Glutamato Metabotropico 5/genéticaRESUMEN
MK-6186 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) which displays subnanomolar potency against wild-type (WT) virus and the two most prevalent NNRTI-resistant RT mutants (K103N and Y181C) in biochemical assays. In addition, it showed excellent antiviral potency against K103N and Y181C mutant viruses, with fold changes (FCs) of less than 2 and 5, respectively. When a panel of 12 common NNRTI-associated mutant viruses was tested with MK-6186, only 2 relatively rare mutants (Y188L and V106I/Y188L) were highly resistant, with FCs of >100, and the remaining viruses showed FCs of <10. Furthermore, a panel of 96 clinical virus isolates with NNRTI resistance mutations was evaluated for susceptibility to NNRTIs. The majority (70%) of viruses tested displayed resistance to efavirenz (EFV), with FCs of >10, whereas only 29% of the mutant viruses displayed greater than 10-fold resistance to MK-6186. To determine whether MK-6186 selects for novel resistance mutations, in vitro resistance selections were conducted with one isolate each from subtypes A, B, and C under low-multiplicity-of-infection (MOI) conditions. The results showed a unique mutation development pattern in which L234I was the first mutation to emerge in the majority of the experiments. In resistance selection under high-MOI conditions with subtype B virus, V106A was the dominant mutation detected in the breakthrough viruses. More importantly, mutant viruses selected by MK-6186 showed FCs of <10 against EFV or etravirine (ETR), and the mutant viruses containing mutations selected by EFV or ETR were sensitive to MK-6186 (FCs of <10).
Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/enzimología , Inhibidores de la Transcriptasa Inversa/farmacología , Alquinos , Benzoxazinas/farmacología , Ciclopropanos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , VIH-1/genética , MutaciónRESUMEN
A new class of indazole-derived bradykinin B(1) antagonists and their structure-activity relationships (SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human B(1) receptor and possess acceptable P-gp and pharmacokinetics properties.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Indazoles/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Humanos , Indazoles/farmacocinética , Unión Proteica , Relación Estructura-ActividadRESUMEN
Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.
Asunto(s)
Fármacos Anti-VIH/química , Éteres/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Pirazoles/química , Piridinas/química , Inhibidores de la Transcriptasa Inversa/química , Regulación Alostérica , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Perros , Éteres/síntesis química , Éteres/farmacocinética , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , Humanos , Mutación , Pirazoles/síntesis química , Pirazoles/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Relación Estructura-ActividadRESUMEN
Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.
Asunto(s)
Éteres/química , Éteres/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Animales , Línea Celular , Perros , Éteres/síntesis química , Éteres/farmacocinética , VIH-1/enzimología , Humanos , Macaca mulatta , Nucleósidos/química , Ratas , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.
Asunto(s)
Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Quinolinas/química , Inhibidores de la Transcriptasa Inversa/química , Sitio Alostérico , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Sitios de Unión , Cristalografía por Rayos X , Transcriptasa Inversa del VIH/metabolismo , Conformación Molecular , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/metabolismo , Quinolinas/síntesis química , Quinolinas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Tiocarbamatos/química , Tiocarbamatos/farmacologíaRESUMEN
Selective bradykinin (BK) B 1 receptor antagonists could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure activity relationships of the structurally novel HTS lead compound 1 provided potent hBK B 1 receptor antagonists with excellent receptor occupancy in the CNS of hBK B 1 transgenic rats.
Asunto(s)
Aminas/química , Benzofenonas/química , Benzofenonas/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Animales , Benzofenonas/síntesis química , Línea Celular , Perros , Humanos , Estructura Molecular , Ratas , Receptor de Bradiquinina B1/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 5-amino derivatives of 8-hydroxy[1,6]-naphthyridine-7-carboxamide exhibiting sub-micromolar potency against replication of HIV-1 in cell culture was identified. One of these analogs, compound 12, displayed excellent pharmacokinetic properties when dosed orally in rats and in monkeys. This compound was demonstrated to be efficacious against replication of simian-human immunodeficiency virus (SHIV) 89.6P in infected rhesus macaques.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , Naftiridinas/química , Naftiridinas/farmacología , Aminación , Inhibidores de Integrasa VIH/química , Estructura Molecular , Naftiridinas/síntesis química , Relación Estructura-ActividadRESUMEN
We describe the efficacy of L-870812, an inhibitor of HIV-1 and SIV integrase, in rhesus macaques infected with the simian-human immunodeficiency virus (SHIV) 89.6P. When initiated before CD4 cell depletion, L-870812 therapy mediated a sustained suppression of viremia, preserving CD4 levels and permitting the induction of virus-specific cellular immunity. L-870812 was also active in chronic infection; however, the magnitude and durability of the effect varied in conjunction with the pretreatment immune response and viral load. These studies demonstrate integrase inhibitor activity in vivo and suggest that cellular immunity facilitates chemotherapeutic efficacy in retroviral infections.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/inmunología , VIH-1/fisiología , Inhibidores de Integrasa/uso terapéutico , Naftiridinas/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Síndrome de Inmunodeficiencia Adquirida/virología , Animales , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Farmacorresistencia Viral , Integrasa de VIH/genética , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/sangre , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/uso terapéutico , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/genética , Inmunidad Celular , Inhibidores de Integrasa/administración & dosificación , Inhibidores de Integrasa/sangre , Inhibidores de Integrasa/farmacología , Integrasas/genética , Integrasas/metabolismo , Leucocitos Mononucleares/virología , Macaca mulatta , Mutación , Naftiridinas/administración & dosificación , Naftiridinas/sangre , Naftiridinas/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/enzimología , Virus de la Inmunodeficiencia de los Simios/genética , Carga Viral , Viremia/tratamiento farmacológico , Replicación Viral/efectos de los fármacosRESUMEN
The increasing incidence of resistance to current HIV-1 therapy underscores the need to develop antiretroviral agents with new mechanisms of action. Integrase, one of three viral enzymes essential for HIV-1 replication, presents an important yet unexploited opportunity for drug development. We describe here the identification and characterization of L-870,810, a small-molecule inhibitor of HIV-1 integrase with potent antiviral activity in cell culture and good pharmacokinetic properties. L-870,810 is an inhibitor with an 8-hydroxy-(1,6)-naphthyridine-7-carboxamide pharmacophore. The compound inhibits HIV-1 integrase-mediated strand transfer, and its antiviral activity in vitro is a direct consequence of this ascribed effect on integration. L-870,810 is mechanistically identical to previously described inhibitors from the diketo acid series; however, viruses selected for resistance to L-870,810 contain mutations (integrase residues 72, 121, and 125) that uniquely confer resistance to the naphthyridine. Conversely, mutations associated with resistance to the diketo acid do not engender naphthyridine resistance. Importantly, the mutations associated with resistance to each of these inhibitors map to distinct regions within the integrase active site. Therefore, we propose a model of the two inhibitors that is consistent with this observation and suggests specific interactions with discrete binding sites for each ligand. These studies provide a structural basis and rationale for developing integrase inhibitors with the potential for unique and nonoverlapping resistance profiles.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Naftiridinas/farmacología , Animales , Células Cultivadas , Perros , Resistencia a Múltiples Medicamentos , Farmacorresistencia Viral , Integrasa de VIH/genética , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/química , VIH-1/enzimología , VIH-1/genética , VIH-2/efectos de los fármacos , Humanos , Macaca mulatta , Masculino , Mutagénesis Sitio-Dirigida , Naftiridinas/química , Ratas , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Linfocitos T/citología , Linfocitos T/virología , Integración Viral/efectos de los fármacosRESUMEN
Since the beginning of the HIV epidemic almost 70 million people have been infected with HIV. It is estimated that 42 million people are currently living with HIV/AIDS. The spread of HIV continues throughout the world and current estimates indicate that in 2002, 5 million people were newly infected with HIV and 3 million people died. Current treatments employ a combination of therapeutic agents that target the viral reverse transcriptase and protease enzymes and viral entry. However the clinical benefit of these agents is often limited due to issues of regimen compliance, significant side effects, and the emergence of viral strains that are drug resistant. The introduction of novel agents that interfere with alternate stages in the viral life cycle represent potential solutions to these problems. The integration of the HIV genome into the cellular chromosome, a process catalyzed by the viral enzyme integrase, has been shown to be essential for viral replication. Since HIV integrase has no direct cellular counterpart it presents itself as an attractive target for therapeutic intervention. This review summarizes recent and promising developments both in the HIV integrase field and the global quest for therapeutically useful inhibitors of HIV integrase.