RESUMEN
1. Due to its unique C-C and C-H bonding properties, conformational preferences and relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery to modulate potency and drug-like properties. During an effort to discover inhibitors of the hepatitis C virus non-structural protein 5B with improved potency and genotype-coverage profiles, the use of a pyrimidinylcyclopropylbenzamide moiety linked to a C6-substituted benzofuran or azabenzofuran core scaffold was explored in an effort to balance antiviral potency and metabolic stability. 2. In vitro metabolism studies of two compounds from this C6-substituted series revealed an NADPH-dependent bioactivation pathway leading to the formation of multiple glutathione (GSH) conjugates. Analysis of these conjugates by LC-MS and NMR demonstrated that the cyclopropyl group was the site of bioactivation. Based on the putative structures and molecular weights of the cyclopropyl-GSH conjugates, a multi-step mechanism was proposed to explain the formation of these metabolites by P450. This mechanism involves hydrogen atom abstraction to form a cyclopropyl radical, followed by a ring opening rearrangement and reaction with GSH. 3. These findings provided important information to the medicinal chemistry team which responded by replacing the cyclopropyl ring with a gem-dimethyl group. Subsequent compounds bearing this feature were shown to avert the bioactivation pathways in question.
Asunto(s)
Antivirales , Benzamidas , Sistema Enzimático del Citocromo P-450/metabolismo , Hepacivirus , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Benzamidas/farmacocinética , Benzamidas/farmacología , Humanos , RatasRESUMEN
Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
Asunto(s)
Compuestos de Fenilurea/química , Inhibidores de Agregación Plaquetaria/química , Antagonistas del Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazoles/química , Urea/análogos & derivados , Administración Oral , Animales , Perros , Semivida , Macaca fascicularis , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/farmacología , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Ratas , Receptores Purinérgicos P2Y1/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Tiazoles/uso terapéutico , Trombosis/tratamiento farmacológico , Urea/farmacocinética , Urea/farmacología , Urea/uso terapéuticoRESUMEN
In solving the P-gp and BCRP transporter-mediated efflux issue in a series of benzofuran-derived pan-genotypic palm site inhibitors of the hepatitis C virus NS5B replicase, it was found that close attention to physicochemical properties was essential. In these compounds, where both molecular weight (MW >579) and TPSA (>110 Å2) were high, attenuation of polar surface area together with weakening of hydrogen bond acceptor strength of the molecule provided a higher intrinsic membrane permeability and more desirable Caco-2 parameters, as demonstrated by trifluoroacetamide 11 and the benchmark N-ethylamino analog 12. In addition, the tendency of these inhibitors to form intramolecular hydrogen bonds potentially contributes favorably to the improved membrane permeability and absorption. The functional group minimization that resolved the efflux problem simultaneously maintained potent inhibitory activity toward a gt-2 HCV replicon due to a switching of the role of substituents in interacting with the Gln414 binding pocket, as observed in gt-2a NS5B/inhibitor complex cocrystal structures, thus increasing the efficiency of the optimization. Noteworthy, a novel intermolecular S=O···C=O n â π* type interaction between the ligand sulfonamide oxygen atom and the carbonyl moiety of the side chain of Gln414 was observed. The insights from these structure-property studies and crystallography information provided a direction for optimization in a campaign to identify second generation pan-genotypic NS5B inhibitors.
RESUMEN
GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Crisenos/química , Morfolinas/química , Relación Estructura-Actividad , Triterpenos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Administración Oral , Animales , Fármacos Anti-VIH/farmacocinética , Ácido Benzoico/química , Disponibilidad Biológica , Técnicas de Química Sintética , Crisenos/farmacología , Perros , Diseño de Fármacos , Estabilidad de Medicamentos , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos , Ratones Noqueados , Microsomas Hepáticos/efectos de los fármacos , Morfolinas/farmacología , Polimorfismo Genético , Ratas Sprague-Dawley , Triterpenos/farmacologíaRESUMEN
Iterative structure-activity analyses in a class of highly functionalized furo[2,3-b]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (14), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (14) is described.
RESUMEN
The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 (43) as a preclinical candidate.
RESUMEN
HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.
RESUMEN
BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.
RESUMEN
A series of natural product analogues based on helioxanthin (2), with particular attention to modification of the lactone ring and methylenedioxy group, were synthesized and evaluated for their antiviral activities. Among them, lactam derivative 18 and helioxanthin cyclic hydrazide 28 exhibited significant in vitro antiviral activity against hepatitis B virus (EC(50) = 0.08 and 0.03 microM, respectively). Compound 18 showed the most potent antiviral activity against hepatitis C virus (55% inhibition at 1.0 microM). Compound 12, an acid-hydrolyzed product of helioxanthin cyclic imide derivative 9, was found to exhibit broad-spectrum antiviral activity against hepatitis B virus (EC(50) = 0.8 microM), herpes simplex virus type 1 (EC(50) = 0.15 microM) and type 2 (EC(50) < 0.1 microM), Epstein-Barr virus (EC(50) = 9.0 microM), and cytomegalovirus (EC(50) = 0.45 microM). Helioxanthin lactam derivative 18 also showed marked inhibition of herpes simplex virus type 1 (EC(50) = 0.29 microM) and type 2 (EC(50) = 0.16 microM). The cyclic hydrazide derivative of helioxanthin 28 and its brominated product 42 exhibited moderately potent activities against human immunodeficiency virus (EC(50) = 2.7 and 2.5 microM, respectively). Collectively, these molecules represent a novel set of antiviral compounds with unique structural features.
Asunto(s)
Antivirales/síntesis química , Benzofuranos/síntesis química , Dioxoles/síntesis química , Lactonas/síntesis química , Lignanos/química , Naftalenos/síntesis química , Antivirales/química , Antivirales/farmacología , Benzofuranos/química , Benzofuranos/farmacología , Citomegalovirus/efectos de los fármacos , Dioxoles/química , Dioxoles/farmacología , VIH/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Herpesvirus Humano 4/efectos de los fármacos , Lactonas/química , Lactonas/farmacología , Naftalenos/química , Naftalenos/farmacología , Relación Estructura-ActividadRESUMEN
Chronic hepatitis B virus (HBV) infection continues to be an important worldwide cause of morbidity and mortality. All the currently approved therapeutic drugs have their limitations: interferon-alpha (IFN-alpha) has limited efficacy and a high incidence of adverse effects; nucleoside analogues are very efficient HBV DNA inhibitors, but resistance occurs eventually. Therefore, it is important to develop new non-nucleoside/nucleotide agents with different modes of action that can be used for antiviral combination therapy. Here, we report on a novel class of compounds, helioxanthin and its derivative 5-4-2, which had potent anti-HBV activities in HepG2.2.15 cells, with the EC50s of 1 and 0.08 microM, respectively. The lamivudine-resistant HBV, L526M/M550V double mutant strain, was also sensitive to helioxanthin and 5-4-2. This class of compounds not only inhibited HBV DNA, but also decreased HBV mRNA and HBV protein expression. The EC50 of HBV DNA inhibition was consistent with the EC50 of HBV 3.5 Kb transcript inhibition, which was 1 and 0.09 microM for helioxanthin and 5-4-2 respectively. Western blot analysis of cell lysate from HepG2.2.15 cells showed that the core protein expression decreased in a dose-dependent manner after drug treatment. In conclusion, helioxanthin and 5-4-2 are potentially unique new anti-HBV agents, which possess a different mechanism of action from existing therapeutic drugs. Both compounds inhibited HBV RNA and protein expression in addition to inhibiting HBV DNA.
Asunto(s)
Antivirales/antagonistas & inhibidores , Antivirales/toxicidad , Regulación Viral de la Expresión Génica/efectos de los fármacos , Virus de la Hepatitis B/genética , Replicación Viral/efectos de los fármacos , Xantinas/toxicidad , Antivirales/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , ADN Viral/antagonistas & inhibidores , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/fisiología , Humanos , Lignanos , ARN Viral/antagonistas & inhibidores , Relación Estructura-Actividad , Proteínas del Núcleo Viral/antagonistas & inhibidores , Proteínas del Núcleo Viral/genética , Xantinas/antagonistas & inhibidores , Xantinas/químicaRESUMEN
A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D(1) Agonist Containing a Rigid beta-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).
Asunto(s)
Agonistas de Dopamina/síntesis química , Isoquinolinas/síntesis química , Naftoles/síntesis química , Animales , Línea Celular , Cuerpo Estriado/metabolismo , Cristalografía por Rayos X , AMP Cíclico/biosíntesis , Agonistas de Dopamina/farmacología , Técnicas In Vitro , Isoquinolinas/farmacología , Conformación Molecular , Naftoles/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , EstereoisomerismoRESUMEN
The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Imidazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Antivirales/farmacocinética , Área Bajo la Curva , Carbamatos , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Hepacivirus/enzimología , Hepacivirus/fisiología , Imidazoles/química , Imidazoles/farmacocinética , Espectroscopía de Resonancia Magnética , Pirrolidinas , Ratas , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Valina/análogos & derivadosRESUMEN
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
Conditions for attachment of acetyl chloride, benzoyl chloride, and chloromethyl oxalate to the 3-position of 4-, 5-, 6-, or 7-azaindoles were explored. Best results were achieved with an excess of AlCl(3) in CH(2)Cl(2) followed by the addition of an acyl chloride at room temperature.