RESUMEN
Incorporating patient perspectives into clinical studies is recognized as important to the development of high-quality, safe, and effective fit-for-patient medicines. However, no widely accepted methodology to help design more patient-centered studies has been established systematically. TransCelerate Biopharma Inc., a non-profit organization promoting collaboration across biopharmaceutical companies, organized a Patient Experience (PE) Initiative to create tools to intentionally include the patient perspective into the design and implementation of clinical studies. The resulting tools include the Patient Protocol Engagement Toolkit (P-PET), to engage patients early in protocol development, and the Study Participant Feedback Questionnaire (SPFQ), to assess patient experiences during clinical studies. To develop these toolkits, TransCelerate conducted a literature review and identified aspects of clinical studies that patients find either valuable or burdensome, or that affect participation, adherence, and engagement in a clinical study. The concepts identified were refined through elicitation of feedback from patient advisors, clinical study site advisors, and subject matter experts from member companies (MCs) of TransCelerate. This feedback was considered in identifying gaps, defining scientific methodology to understand how to evaluate patients' needs, and developing and refining the P-PET and the SPFQ. As part of the development process, descriptions/drafts of the tools were shared with patients, clinical site advisory groups, MCs, and the US Food and Drug Administration, and then revised. MCs simulated use of the tools, and feedback was incorporated into the final versions of the P-PET and SPFQ prior to public release. The P-PET and SPFQ are available free on the TransCelerate website.
Asunto(s)
Participación del Paciente , Humanos , Atención Dirigida al Paciente , Proyectos de Investigación , Encuestas y Cuestionarios , Estados Unidos , United States Food and Drug AdministrationRESUMEN
From Monoclonal Antibodies for C. difficile Therapy II, no participants (n = 0/69) with a sustained clinical cure through 12 weeks following bezlotoxumab infusion experienced recurrent Clostridioides difficile infection (rCDI) after 9 months (versus actoxumab + bezlotoxumab, n = 2/65; versus placebo, n = 1/34). Bezlotoxumab's efficacy appears to be due to prevention rather than delayed onset of rCDI. Clinical Trials Registration. NCT01513239.
Asunto(s)
Clostridioides difficile , Infecciones por Clostridium , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos ampliamente neutralizantes , Clostridioides , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/prevención & control , Humanos , RecurrenciaRESUMEN
BACKGROUND: The optimum diagnostic test method for Clostridioides difficile infection (CDI) remains controversial due to variation in accuracy in identifying true CDI. This post hoc analysis examined the impact of CDI diagnostic testing methodology on efficacy outcomes in phase 3 MODIFY I/II trials. METHODS: In MODIFY I/II (NCT01241552/NCT01513239), participants received bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment for primary/recurrent CDI (rCDI). Using MODIFY I/II pooled data, initial clinical cure (ICC) and rCDI were assessed in participants diagnosed at baseline using direct detection methods (enzyme immunoassay [EIA]/cell cytotoxicity assay [CCA]) or indirect methods to determine toxin-producing ability (toxin gene polymerase chain reaction [tgPCR]/toxigenic culture). RESULTS: Of 1554 participants who received bezlotoxumab or placebo in MODIFY I/II, 781 (50.3%) and 773 (49.7%) were diagnosed by tgPCR/toxigenic culture and toxin EIA/CCA, respectively. Participants diagnosed by toxin EIA/CCA were more likely to be inpatients, older, and have severe CDI. In bezlotoxumab recipients, ICC rates were slightly higher in the toxin EIA/CCA subgroup (81.7%) vs tgPCR/toxigenic culture (78.4%). Bezlotoxumab significantly reduced the rCDI rate vs placebo in both subgroups; however, the magnitude of reduction was substantially larger in participants diagnosed by toxin EIA/CCA (relative difference, -46.6%) vs tgPCR/toxigenic culture (-29.1%). In bezlotoxumab recipients, the rCDI rate was lower in the toxin EIA/CCA subgroup (17.6%) vs tgPCR/toxigenic culture (23.6%; absolute difference, -6.0%; 95% confidence interval, -12.4 to 0.3; relative difference, -25.4%). CONCLUSIONS: Diagnostic tests that detect fecal C. difficile toxins are of fundamental importance to accurately diagnosing CDI, including in clinical trial design, ensuring that therapeutic efficacy is not underestimated.
RESUMEN
Background: The fully human monoclonal antibody bezlotoxumab binds Clostridioides (Clostridium) difficile toxin B and reduces recurrence rates in patients with C. difficile infection (CDI) receiving antibacterial treatment for a primary or recurrent episode. Objectives: To investigate whether the timing of bezlotoxumab administration relative to the onset of antibacterial treatment affected clinical outcome in the Phase 3 trials MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Methods: Initial clinical cure and CDI recurrence rates of participants who received bezlotoxumab or placebo were summarized by timing of infusion relative to the start of antibacterial drug treatment for CDI: 0-2, 3-4 and ≥5 days after onset. Results: Of 1554 total participants, 649 (41.8%), 469 (30.1%) and 436 (28.1%) received an infusion 0-2, 3-4 and ≥5 days after onset of antibacterial treatment for CDI, respectively. Regardless of timing of administration, there were no differences in initial clinical cure rates between participants receiving bezlotoxumab (range 77.8% to 81.4%) or placebo (77.8% to 81.7%). Bezlotoxumab efficacy was unaffected by timing of administration; rates of CDI recurrence were lower versus placebo in all subgroups (range 19.3% to 22.8% for bezlotoxumab and 31.7% to 35.8% for placebo). Timing of administration also had no effect on time to resolution of diarrhoea, which was achieved by the end of antibacterial treatment in â¼95% of participants in both bezlotoxumab and placebo groups. Conclusions: Bezlotoxumab is effective in preventing CDI recurrence and can be administered at any time before ending antibacterial drug treatment.
Asunto(s)
Antibacterianos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Neutralizantes/administración & dosificación , Antitoxinas/administración & dosificación , Infecciones por Clostridium/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos ampliamente neutralizantes , Terapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Recurrencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS: We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS: In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, -10.1 percentage points; 95% confidence interval [CI], -15.9 to -4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, -9.9 percentage points; 95% CI, -15.5 to -4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, -11.6 percentage points; 95% CI, -17.4 to -5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, -10.7 percentage points; 95% CI, -16.4 to -5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS: Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .).
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Clostridioides difficile , Infecciones por Clostridium/prevención & control , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos ampliamente neutralizantes , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Infusiones Intravenosas , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Prevención Secundaria , Adulto JovenRESUMEN
HIV-1 integrase catalyzes the insertion of viral DNA into the genome of the host cell. Integrase inhibitor N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide selectively inhibits the strand transfer process of integration. 4-Substituted pyrrolidinones possessing various groups on the pyrrolidinone nitrogen were introduced at the 5-position of the naphthyridine scaffold. These analogs exhibit excellent activity against viral replication in a cell-based assay. The preparation of these compounds was enabled by a three-step, two-pot reaction sequence from a common butenolide intermediate.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH-1/efectos de los fármacos , Naftiridinas/síntesis química , Naftiridinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/química , Inhibidores de Integrasa VIH/química , Estructura Molecular , Naftiridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A series of 10-hydroxy-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. Structure-activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study, 16, inhibits integrase strand-transfer activity with an IC(50) value of 10 nM, inhibits HIV-1 replication in cell culture with an IC(95) value of 35 nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (i.v. t(1/2)=5.3 h, F=17%).
Asunto(s)
Química Farmacéutica/métodos , Integrasa de VIH/síntesis química , Integrasa de VIH/farmacología , Integrasas/genética , Mutación , Administración Oral , Animales , Antivirales/farmacología , Disponibilidad Biológica , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Ratas , Relación Estructura-Actividad , Replicación ViralRESUMEN
A series of 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides was synthesized and tested for their inhibition of HIV-1 integrase catalytic activity and HIV-1 replication in cells. Structure-activity studies around lead compound 5 indicated that a coplanar relationship of metal-binding heteroatoms provides optimal binding to the integrase active site. Identification of potency-enhancing substituents and adjustments in lipophilicity provided 17b which inhibits integrase-catalyzed strand transfer with an IC(50) value of 74 nM and inhibits HIV-1 replication in cell culture in the presence of 50% normal human serum with an IC(95) value of 63 nM.
Asunto(s)
Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/efectos de los fármacos , Pirazinas/química , Pirazinas/farmacología , Catálisis , Línea Celular , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/síntesis química , VIH-1/enzimología , VIH-1/fisiología , Pirazinas/síntesis química , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
This Letter describes the design, synthesis, and biological evaluation of novel 3-indole sulfonamides as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) with balanced profiles against common HIV RT mutants K103N and Y181C.
Asunto(s)
Indoles/química , Inhibidores de la Transcriptasa Inversa/farmacología , Sulfonamidas/farmacología , Cristalografía por Rayos X , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , Modelos Moleculares , Mutación , Inhibidores de la Transcriptasa Inversa/química , Sulfonamidas/químicaRESUMEN
A series of potent novel 8-hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 12 is active against replication of HIV-1 in cell culture with a CIC(95) of 0.31microM. Further SAR exploration led to the preparation of pseudosymmetrical tricyclic pyrrolopyrazine inhibitors 23 and 24 with further improvement in antiviral activity.
Asunto(s)
Inhibidores de Integrasa VIH/química , Integrasa de VIH , Pirazinas/química , Línea Celular Tumoral , Integrasa de VIH/fisiología , Inhibidores de Integrasa VIH/farmacología , Humanos , Pirazinas/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimología , Linfocitos T/virologíaRESUMEN
A series of potent novel dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 6 is active against replication of HIV with a CIC(95) of 0.31 microM and exhibits no shift in potency in the presence of 50% normal human serum. It displays a good pharmacokinetic profile when dosed in rats and no covalent binding with microsomal proteins in both in vitro and in vivo models.
Asunto(s)
Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Pirazinas/química , Pirazinas/farmacología , Animales , Benceno/química , Línea Celular , VIH/efectos de los fármacos , VIH/enzimología , VIH/fisiología , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacocinética , Humanos , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Línea Celular , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Indicadores y Reactivos , Indinavir/síntesis química , Indinavir/farmacología , Relación Estructura-ActividadRESUMEN
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacocinética , Naftiridinas/síntesis química , Administración Oral , Animales , Células Cultivadas , Integrasa de VIH/efectos de los fármacos , Integrasa de VIH/genética , Inhibidores de Integrasa VIH/farmacología , Humanos , Concentración 50 Inhibidora , Mutación , Naftiridinas/farmacocinética , Naftiridinas/farmacología , Ratas , 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
Efforts directed to identifying potent HIV protease inhibitors (PI) have yielded a class of compounds that are not only very active against wild-type (NL4-3) HIV virus but also very potent against a panel of PI-resistant viral isolates. Chemistry and biology are described.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , VIH/efectos de los fármacos , Indinavir/análogos & derivados , Administración Oral , Disponibilidad Biológica , Farmacorresistencia Viral , VIH/enzimología , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/administración & dosificación , Estructura MolecularRESUMEN
Simian-human immunodeficiency virus (SHIV) challenge studies in rhesus macaques were conducted to evaluate the efficacy of adenovirus-based vaccines in the context of different major histocompatibility complex class I genetic backgrounds and different vaccine compositions. Mamu-A*01 allele-negative rhesus monkeys were immunized with one of the following vaccine constructs: (i) replication-defective recombinant adenovirus type 5 (Ad5) expressing human immunodeficiency virus type 1 (HIV-1) Tat (Ad5/HIVTat); (ii) Ad5 vector expressing simian immunodeficiency virus (SIV) Gag (Ad5/SIVGag); (iii) Ad5 vector expressing the truncated HIV-1(jrfl) Env, gp140 (Ad5/gp140_jrfl); (iv) Ad5 vector expressing the SHIV-89.6P gp140 (Ad5/gp140_89.6P); or (v) the combination of Ad5/SIVGag and Ad5/gp140_jrfl. Following intravenous challenge with SHIV-89.6P, only those cohorts that received vaccines expressing Gag or Env exhibited an attenuation of the acute viremia and associated CD4-cell lymphopenia. While no prechallenge neutralizing antibody titers were detectable in either Ad5/gp140-vaccinated group, an accelerated neutralizing antibody response was observed in the Ad5/gp140_89.6P-vaccinated group upon viral challenge. The set-point viral loads in the Ad5/SIVGag- and Ad5/gp140_jrfl-vaccinated groups were associated with the overall strength of the induced cellular immune responses. To examine the contribution of Mamu-A*01 allele in vaccine efficacy against SHIV-89.6P challenge, Mamu-A*01-positive monkeys were immunized with Ad5/SIVGag. Vaccine-mediated protection was significantly more pronounced in the Mamu-A*01-positive monkeys than in Mamu-A*01-negative monkeys, suggesting the strong contributions of T-cell epitopes restricted by the Mamu-A*01 molecule. The implications of these results in the development of an HIV-1 vaccine will be discussed.
Asunto(s)
Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Productos del Gen env/inmunología , Productos del Gen gag/inmunología , Productos del Gen tat/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Adenoviridae/genética , Animales , Anticuerpos Antivirales/sangre , Antígenos Virales/genética , Antígenos Virales/inmunología , Recuento de Linfocito CD4 , Modelos Animales de Enfermedad , Productos del Gen env/genética , Productos del Gen tat/genética , Vectores Genéticos , VIH/genética , VIH/inmunología , Inmunidad Celular , Macaca mulatta , Pruebas de Neutralización , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología , Carga Viral , Viremia , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.
Asunto(s)
Compuestos de Bencilo/farmacología , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Naftiridinas/farmacología , Uracilo/análogos & derivados , Replicación Viral/efectos de los fármacos , Animales , Compuestos de Bencilo/química , Compuestos de Bencilo/farmacocinética , Disponibilidad Biológica , Cristalografía por Rayos X , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/fisiología , Naftiridinas/química , Naftiridinas/farmacocinética , Ratas , Uracilo/químicaRESUMEN
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
A series of highly potent HIV protease inhibitors have been designed and synthesized. These compounds are active against various clinical viral isolates as well as wild-type virus. The synthesis and biological activity of these HIV protease inhibitors are discussed.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , Aminas , Fármacos Anti-VIH/farmacología , Línea Celular , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/farmacología , Compuestos Heterocíclicos , Humanos , Concentración 50 Inhibidora , Mutación , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Naphthyridine 7 inhibits the strand transfer of the integration process catalyzed by integrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1 infection in cell culture at 0.39 microM. It does not exhibit cytotoxicity in cell culture at < or =12.5 microM and shows a good pharmacokinetic profile when dosed orally to rats. The antiviral activity of 7 and its effect on integration were confirmed using viruses with specific integrase mutations.