RESUMEN
Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp113 in gp120, the antiviral potency of several analogues met or exceeded that of 3, demonstrating that engaging Asp113 is not a prerequisite for potent antiviral activity.
Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Indoles/farmacología , Acoplamiento Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Humanos , Indoles/síntesis química , Indoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4-d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype viral infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein.
Asunto(s)
Compuestos Aza/química , Benzamidas/química , Descubrimiento de Drogas , Inhibidores de Fusión de VIH/química , Inhibidores de Fusión de VIH/farmacología , VIH-1/efectos de los fármacos , Indoles/química , Piperazinas/química , Tetrahidroisoquinolinas/farmacología , Acoplamiento Viral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Proteína gp120 de Envoltorio del VIH/genética , Inhibidores de Fusión de VIH/síntesis química , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Células HeLa , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/química , Replicación Viral/efectos de los fármacosRESUMEN
A series of HIV-1 attachment inhibitors containing a 4,6-diazaindole core were examined in an effort to identify a compound which improved upon the potency and oral exposure of BMS-488043 (2). BMS-488043 (2) is a 6-azaindole-based HIV-1 attachment inhibitor which established proof-of-concept for this mechanism in human clinical studies but required high doses and concomitant administration of a high fat meal to achieve efficacious exposures. Based on previous studies in indole and azaindole scaffolds, SAR investigation was concentrated around the key 7-position in the 4,6-diazaindole series and led to the discovery of molecules with 5- to 20-fold increases in potency and three- to seven-fold increases in exposure over 2 in a rat PK studies.
Asunto(s)
Fármacos Anti-VIH/química , Compuestos Aza/química , VIH-1/metabolismo , Indoles/química , Administración Oral , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Evaluación Preclínica de Medicamentos , VIH-1/efectos de los fármacos , Semivida , Humanos , Piperazinas/química , Piperazinas/farmacocinética , Ácido Pirúvico , Ratas , Relación Estructura-Actividad , Acoplamiento Viral/efectos de los fármacosRESUMEN
A series of 4-azaindole oxoacetic acid piperazine benzamides was synthesized and evaluated in an effort to identify an oral HIV-1 attachment inhibitor with the potential to improve upon the pre-clinical profile of BMS-378806 (7), an initial clinical compound. Modifications at the 7-position of the 4-azaindole core modulated potency significantly and SAR showed that certain compounds with a 5-membered ring heteroaryl group at that position were the most potent. Four of the compounds with the best profiles were evaluated in a rat pharmacokinetic model and all had superior oral bioavailability and lower clearance when compared with 7.
Asunto(s)
Fármacos Anti-VIH/química , VIH-1/metabolismo , Indoles/química , Administración Oral , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos , VIH-1/efectos de los fármacos , Semivida , Humanos , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Relación Estructura-Actividad , Acoplamiento Viral/efectos de los fármacosRESUMEN
BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4(+) T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC(50)) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.
Asunto(s)
Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Células Cultivadas , Células HCT116 , VIH/efectos de los fármacos , VIH/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , Células HeLa , Células Hep G2 , HumanosRESUMEN
Attachment inhibitors (AI) are a novel class of HIV-1 antivirals, with little information available on clinical resistance. BMS-488043 is an orally bioavailable AI that binds to gp120 of HIV-1 and abrogates its binding to CD4(+) lymphocytes. A clinical proof-of-concept study of the AI BMS-488043, administered as monotherapy for 8 days, demonstrated significant viral load reductions. In order to examine the effects of AI monotherapy on HIV-1 sensitivity, phenotypic sensitivity assessment of baseline and postdosing (day 8) samples was performed. These analyses revealed that four subjects had emergent phenotypic resistance (a 50% effective concentration [EC(50)] >10-fold greater than the baseline value) and four had high baseline EC(50)s (>200 nM). Population sequencing and sequence determination of cloned envelope genes uncovered five gp120 mutations at four loci (V68A, L116I, S375I/N, and M426L) associated with BMS-488043 resistance. Substitution at the 375 locus, located near the CD4 binding pocket, was the most common (maintained in 5/8 subjects at day 8). The five substitutions were evaluated for their effects on AI sensitivity through reverse genetics in functional envelopes, confirming their role in decreasing sensitivity to the drug. Additional analyses revealed that these substitutions did not alter sensitivity to other HIV-1 entry inhibitors. Thus, our studies demonstrate that although the majority of the subjects' viruses maintained sensitivity to BMS-488043, substitutions can be selected that decrease HIV-1 susceptibility to the AI. Most importantly, the substitutions described here are not associated with resistance to other approved antiretrovirals, and therefore, attachment inhibitors could complement the current arsenal of anti-HIV agents.
Asunto(s)
Farmacorresistencia Viral , Inhibidores de Fusión de VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Piperazinas/farmacología , Secuencia de Aminoácidos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Antígenos CD4/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/administración & dosificación , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/virología , VIH-1/genética , Humanos , Indoles , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Datos de Secuencia Molecular , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Reacción en Cadena de la Polimerasa , Ácido Pirúvico , Análisis de Secuencia de ADN , Resultado del TratamientoRESUMEN
We demonstrate that HIV attachment inhibitors (AIs) prevent HIV envelope-induced destruction of two neuronal cell lines (SH-SY5Y and BE(2)-M17) at low nanomolar concentrations. The fusion inhibitor enfuvirtide and the CCR5 inhibitors UK427,857 and TAK779 do not display protection activity, suggesting the involvement of Env/cell interaction site(s) distinct from the sites involved in the viral entry process. We surmise that by inducing conformation changes in the envelope, AIs likely obstruct novel interactions with a neuronal cell factor(s) required for induction of apoptosis. This antiretroviral class may therefore have the potential to inhibit HIV-induced neuron damage, thereby curtailing the increasing incidence of HIV-associated cognitive impairment.
Asunto(s)
Proteína gp120 de Envoltorio del VIH/fisiología , Inhibidores de Fusión de VIH/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Muerte Celular , Humanos , Indoles , Neuronas/patología , Piperazinas/farmacología , Ácido PirúvicoRESUMEN
Human immunodeficiency virus type 1 (HIV-1) envelope (Env) binding induces proapoptotic signals in CD4(+) T cells without a requirement of infection. Defective virus particles, which represent the majority of HIV-1, usually contain a functional Env and therefore represent a potentially significant cause of such CD4(+)-T-cell loss. We reasoned that an HIV-1 inhibitor that prohibits Env-host cell interactions could block the destructive effects of defective particles. HIV-1 attachment inhibitors (AIs), which potently inhibit Env-CD4 binding and subsequent downstream effects of Env, display low-nanomolar antiapoptotic potency and prevent CD4(+)-T-cell depletion from mixed lymphocyte cultures, also with low-nanomolar potency. Specific Env amino acid changes that confer resistance to AI antientry activity eliminate AI antiapoptotic effects. We observed that CD4(+)-T-cell destruction is specific for CXCR4-utilizing HIV-1 strains and that the fusion blocker enfuvirtide inhibits Env-mediated CD4(+)-T-cell killing but is substantially less potent than AIs. These observations, in conjunction with observed antiapoptotic activities of soluble CD4 and the CXCR4 blocker AMD3100, suggest that this AI activity functions through a mechanism common to AI antientry activity, e.g., prevention of Env conformation changes necessary for specific interactions with cellular factors that facilitate viral entry. Our study suggests that AIs, in addition to having potent antientry activity, could contribute to immune system homeostasis in individuals infected with HIV-1 that can engage CXCR4, thereby mitigating the increased risk of adverse clinical events observed in such individuals on current antiretroviral regimens.
Asunto(s)
Fármacos Anti-VIH/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , VIH-1/efectos de los fármacos , Proteínas del Envoltorio Viral/fisiología , Acoplamiento Viral/efectos de los fármacos , Apoptosis/efectos de los fármacos , Humanos , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/fisiología , Virión/efectos de los fármacos , Virión/fisiologíaRESUMEN
1-(4-Benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1a) has been characterized as an inhibitor of HIV-1 attachment that interferes with the interaction of viral gp120 with the host cell receptor CD4. In previous studies, the effect of indole substitution pattern on antiviral activity was probed. In this Letter, the effect of structural variation of the benzamide moiety is described, a study that reveals the potential or the phenyl moiety to be replaced by five-membered heterocyclic rings and a restricted tolerance for the introduction of substituents to the phenyl ring.
Asunto(s)
Fármacos Anti-VIH/química , Benzamidas/química , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Inhibidores de Fusión de VIH/química , Indoles/química , Piperazinas/química , Acoplamiento Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Línea Celular , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/síntesis química , Inhibidores de Fusión de VIH/farmacología , Humanos , Indoles/síntesis química , Indoles/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
4-Fluoro- and 4-methoxy-1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (2 and 3, respectively) have been characterized as potent inhibitors of HIV-1 attachment that interfere with the interaction of viral gp120 with the host cell receptor CD4. As part of an effort to understand fundamental aspects of this pharmacophore, discovered originally using a high throughput cell-based screen, modification and substitution of the piperazine ring was examined in the context of compounds 6a-ah. The piperazine ring was shown to be a critical element of the HIV-1 attachment inhibiting pharmacophore, acting as a scaffold to deploy the indole glyoxamide and benzamide in a topographical relationship that complements the binding site on gp120.
Asunto(s)
Fármacos Anti-VIH/química , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Indoles/química , Piperazinas/química , Acoplamiento Viral/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Línea Celular , Proteína gp120 de Envoltorio del VIH/metabolismo , Humanos , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.
Asunto(s)
Inhibidores de Fusión de VIH/química , Inhibidores de Fusión de VIH/farmacología , VIH-1/efectos de los fármacos , Indoles/farmacología , Acoplamiento Viral/efectos de los fármacos , Animales , Línea Celular , Perros , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/prevención & control , Humanos , Indoles/química , Indoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
Asunto(s)
Guanina/análogos & derivados , VIH-1/efectos de los fármacos , Antivirales/farmacología , Línea Celular , Guanina/farmacología , Infecciones por VIH/tratamiento farmacológico , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , HumanosRESUMEN
The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with 1 to deliver temsavir (3, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp2-hybridized heteroaryl rings at the 7-position of the heterocyclic nucleus. Compounds that adhered to a coplanarity model afforded targeted antiviral potency, leading to the identification of 3 with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of 3 limited plasma exposure at higher doses, both in preclinical studies and in clinical trials as the result of dissolution- and/or solubility-limited absorption, a deficiency addressed by the preparation of the phosphonooxymethyl prodrug 4 (BMS-663068, fostemsavir). An extended-release formulation of 4 is currently in phase III clinical trials where it has shown promise as part of a drug combination therapy in highly treatment-experienced HIV-1 infected patients.
Asunto(s)
Descubrimiento de Drogas , VIH-1/efectos de los fármacos , VIH-1/fisiología , Organofosfatos/metabolismo , Piperazinas/metabolismo , Piperazinas/farmacología , Profármacos/metabolismo , Triazoles/farmacología , Acoplamiento Viral/efectos de los fármacos , Animales , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Células CACO-2 , Membrana Celular/metabolismo , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Organofosfatos/farmacología , Permeabilidad , Profármacos/farmacología , Conformación Proteica , Ratas , Triazoles/metabolismoRESUMEN
The HIV-1 gp120 envelope protein is an essential component in the multi-tiered viral entry process. Despite the overall genetic heterogeneity of the gp120 glycoprotein, the conserved CD4 binding site provides an attractive antiviral target. Recently, increased efforts aimed at the development of inhibitors of gp120 have been reported. This review focuses primarily on small-molecule gp120 inhibitors and discusses key characteristics of compounds that appear to fall within this class. The preclinical profiles of compounds that prevent gp120 from assuming a conformation favorable for CD4 binding are described in this review. In addition, inhibitors possessing some common structural features, including at least one compound that exhibits sub-nanomolar potency in a cell fusion assay are discussed. A series of compounds that were designed to enhance immune responses to virus via alteration of the gp120 conformation after targeting the CD4 binding pocket are also described. The efficacy of gp120 inhibitors as a microbicide to prevent sexual HIV transmission in the rhesus macaque model is discussed. Results suggest that this class of compounds may have value if included in a microbicide cocktail with inhibitors of alternate mechanisms. Importantly, preliminary results from clinical studies of orally administered BMS-488043 demonstrate that antiviral efficacy can be achieved in humans with a CD4-attachment inhibitor that targets gp120.
Asunto(s)
Proteína gp120 de Envoltorio del VIH/fisiología , Inhibidores de Fusión de VIH/farmacología , VIH-1/fisiología , Diseño de Fármacos , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , HumanosRESUMEN
Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/metabolismo , Indoles/farmacología , Piperazinas/farmacología , Administración Oral , Animales , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Antagonistas de los Receptores CCR5 , Perros , Humanos , Indoles/química , Indoles/farmacocinética , Infusiones Intravenosas , Macaca fascicularis , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Receptores CXCR4/antagonistas & inhibidoresRESUMEN
A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C-linked heterocycles (12c-l), and N-linked heterocycles (12m-u) provided compounds with subnanomolar potency in a pseudotype infectivity assay and good pharmacokinetic profiles in vivo. A predictive model was developed from the initial SAR in which the potency of the analogues correlated with the ability of the substituent in the 7-position of the azaindole to adopt a coplanar conformation by either forming internal hydrogen bonds or avoiding repulsive substitution patterns. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248, 12m) exhibited much improved in vitro potency and pharmacokinetic properties than the previous clinical candidate BMS-488043 (1). The predicted low clearance in humans, modest protein binding, and good potency in the presence of 40% human serum for 12m led to its selection for human clinical studies.
Asunto(s)
Fármacos Anti-VIH/síntesis química , VIH-1/efectos de los fármacos , Indoles/síntesis química , Piperazinas/síntesis química , Piridinas/síntesis química , Pirroles/síntesis química , Triazinas/síntesis química , Triazoles/síntesis química , Animales , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Células CACO-2 , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , VIH-1/fisiología , Humanos , Indoles/farmacocinética , Indoles/farmacología , Microsomas Hepáticos/metabolismo , Piperazinas/farmacocinética , Piperazinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Teoría Cuántica , Ratas , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/farmacología , Triazoles/farmacocinética , Triazoles/farmacología , Acoplamiento Viral/efectos de los fármacosRESUMEN
BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.
Asunto(s)
Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Organofosfatos/farmacología , Piperazinas/farmacología , Profármacos/farmacología , Acoplamiento Viral/efectos de los fármacos , Administración Oral , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Grasas de la Dieta/administración & dosificación , Perros , Interacciones Alimento-Droga , VIH-1/fisiología , Haplorrinos , Humanos , Indoles , Organofosfatos/química , Organofosfatos/farmacocinética , Piperazinas/química , Piperazinas/farmacocinética , Profármacos/química , Profármacos/farmacocinética , Ácido Pirúvico , Ratas , SolubilidadRESUMEN
Treatment with HIV attachment inhibitors (AIs) can select for escape mutants throughout the viral envelope. We report on three such mutations: F423Y (gp120 CD4 binding pocket) and I595F and K655E (gp41 ectodomain). Each displayed decreased sensitivity to the AI BMS-488043 and earlier generation AIs, along with increased sensitivity to the broadly neutralizing antibodies 2F5 and 4E10, without affecting the rate of viral entry or sensitivity to the entry inhibitors AMD-3100 and Enfuvirtide. We also observed that I595F did not substantially increase envelope sensitivity to HIV-infected patient sera. Based on these observations, we propose that although F423Y, I595F and K655E may all affect the presentation of the 2F5 and 4E10 epitopes, natural immune mimicry is rare only for the I595F effect. Thus, it seems that in addition to restricting AI resistance development, incorporation of I595F into an appropriate vehicle could elicit a novel antiviral response to improve vaccine efficacy.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Farmacorresistencia Viral , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/inmunología , Mutación Missense , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp41 de Envoltorio del VIH/genética , Proteína gp41 de Envoltorio del VIH/inmunología , Inhibidores de Fusión de VIH/farmacología , VIH-1/aislamiento & purificación , Humanos , Indoles , Estructura Molecular , Pruebas de Neutralización , Piperazinas/farmacología , Ácido PirúvicoRESUMEN
Optimizing pharmacokinetic properties to improve oral exposure is a common theme in modern drug discovery. In the present work, in vitro Caco-2 permeability and microsomal half-life screens were utilized in an effort to guide the structure-activity relationship in order to improve the pharmacokinetic properties of novel HIV-1 attachment inhibitors. The relevance of the in vitro screens to in vivo pharmacokinetic properties was first demonstrated with a number of program compounds at the early stage of lead optimization. The Caco-2 permeability, tested at 200 microM, was quantitatively predictive of in vivo oral absorption, with complete absorption occurring at a Caco-2 permeability of 100 nm/s or higher. The liver microsomal half-life screen, conducted at 1 microM substrate concentration, can readily differentiate low-, intermediate-, and high-clearance compounds in rats, with a nearly 1:1 correlation in 12 out of 13 program compounds tested. Among the >100 compounds evaluated, BMS-488043 emerged as a lead, exhibiting a Caco-2 permeability of 178 nm/s and a microsomal half-life predictive of a low clearance (4 mL/min/kg) in humans. These in vitro characteristics translated well to the in vivo setting. The oral bioavailability of BMS-488043 in rats, dogs, and monkeys was 90%, 57%, and 60%, respectively. The clearance was low in all three species tested, with a terminal half-life ranging from 2.4 to 4.7 h. Furthermore, the oral exposure of BMS-488043 was significantly improved (6- to 12-fold in rats and monkeys) compared to the prototype compound BMS-378806 that had a suboptimal Caco-2 permeability (51 nm/s) and microsomal half-life. More importantly, the improvements in preclinical pharmacokinetics translated well to humans, leading to a >15-fold increase in the human oral exposure of BMS-488043 than BMS-378806 and enabling a clinical proof-of-concept for this novel class of anti-HIV agents. The current studies demonstrated the valuable role of in vitro ADME screens in improving oral pharmacokinetics at the lead optimization stage.
Asunto(s)
Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacocinética , Permeabilidad de la Membrana Celular , Inhibidores de Fusión de VIH/metabolismo , Inhibidores de Fusión de VIH/farmacocinética , Microsomas Hepáticos/metabolismo , Piperazinas/metabolismo , Piperazinas/farmacocinética , Administración Oral , Animales , Fármacos Anti-VIH/química , Células CACO-2 , Perros , Inhibidores de Fusión de VIH/química , Semivida , Haplorrinos , Humanos , Indoles , Masculino , Piperazinas/química , Ácido Pirúvico , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.