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1.
Bioorg Med Chem Lett ; 28(1): 43-48, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29162454

RESUMEN

Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.


Asunto(s)
Antivirales/química , Compuestos Macrocíclicos/química , Naftalenos/química , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/farmacología , Evaluación Preclínica de Medicamentos , Semivida , Corazón/efectos de los fármacos , Corazón/fisiología , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Microsomas Hepáticos/metabolismo , Conformación Molecular , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Conejos , Ratas , Proteínas no Estructurales Virales/metabolismo
2.
Bioorg Med Chem Lett ; 27(3): 590-596, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28011221

RESUMEN

The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relating to structure-activity relationships as well as the pharmacokinetic and cardiovascular profiles of these analogues is provided.


Asunto(s)
Antivirales/química , Hepacivirus/enzimología , Oligopéptidos/química , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Semivida , Corazón/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Técnicas In Vitro , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Prolina/química , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Conejos , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Proteínas no Estructurales Virales/metabolismo
3.
Bioorg Med Chem Lett ; 27(15): 3294-3300, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28633899

RESUMEN

The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.


Asunto(s)
Antivirales/química , Antivirales/farmacología , Benzazepinas/química , Benzazepinas/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Benzazepinas/farmacocinética , Perros , Haplorrinos , Hepacivirus/enzimología , Hepacivirus/metabolismo , Hepatitis C/virología , Humanos , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/metabolismo , Ratas , Proteínas no Estructurales Virales/metabolismo
4.
Rapid Commun Mass Spectrom ; 30(15): 1787-96, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27426455

RESUMEN

RATIONALE: It is well known that the organic anion transporting polypeptide 1B1 (OATP1B1) plays a major role in the hepatic uptake of a range of drugs. To this end, it is pivotal that the potential for new molecular entities (NMEs) to inhibit OATP1B1 activity be assessed during early drug discovery. The work reported herein describes the development of a high-throughput analytical method to measure the clinically relevant probe substrate, pitavastatin, for the in vitro assessment of OATP1B1 inhibition. METHODS: Development of an analytical method capable of very fast throughput was crucial for the success of this assay and was accomplished using a system which combines direct, on-line solid-phase extraction (SPE) with highly sensitive, label-free tandem mass spectrometry (MS/MS)-based detection. Mass spectrometry analysis of pitavastatin, along with the stable isotopically labeled internal standard d5-pitavastatin, was conducted using positive electrospray ionization (ESI) in selected reaction monitoring (SRM) mode. RESULTS: The on-line SPE-MS/MS platform demonstrated similar sensitivity, selectivity, reproducibility, linearity and robustness to existing methodologies while achieving analytical cycle times of 10.4 seconds per well. Sensitivity exceeded what was necessary for our assay conditions, with a determined lower limit of quantification (LLOQ) for pitavastatin of 10 pM (picomolar) in assay matrix. Furthermore, the potency of multiple reference compounds was shown to be within 2-fold of IC50 values generated from liquid chromatography (LC)/MS/MS-based literature values. CONCLUSIONS: A very fast and robust analytical method was successfully developed for the measurement of the clinically relevant OATP1B1 substrate, pitavastatin. The successful development and implementation of this very important early liability screen has helped to facilitate judicious lead candidate progression and will ultimately help build a greater understanding of OATP1B1-NME interactions, in general. Copyright © 2016 John Wiley & Sons, Ltd.


Asunto(s)
Cromatografía Liquida , Descubrimiento de Drogas , Transportador 1 de Anión Orgánico Específico del Hígado/efectos de los fármacos , Espectrometría de Masas en Tándem , Humanos , Reproducibilidad de los Resultados , Extracción en Fase Sólida
5.
Bioorg Med Chem Lett ; 24(8): 1993-7, 2014 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-24656612

RESUMEN

Efforts investigating spatially comparative alternates of the ethylene-bridged piperazine in BMS-791325 that would offer a maintained or improved virologic and pharmacokinetic profile have been multifaceted. One foray involved the utilization of various octahydropyrrolo[3,4-c]pyrrole propellanes. Many of the propellane analogs described in this work exhibited better than targeted potency (less than 20 nM). Additionally, improved exposure in rats was achieved through the employment of two newly invented and now readily accessible carbon bridged propellanes as compared to their heteroatom bridged analogs.


Asunto(s)
Antivirales/química , Antivirales/farmacocinética , Hepacivirus , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Benzazepinas/química , Indoles/química , Estructura Molecular , Ratas
6.
Toxicol Sci ; 194(2): 235-245, 2023 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-37261863

RESUMEN

BMS-932481 was designed to modulate ɣ-secretase activity to produce shorter and less amyloidogenic peptides, potentially averting liabilities associated with complete enzymatic inhibition. Although it demonstrated the intended pharmacology in the clinic, BMS-932481 unexpectedly caused drug-induced liver injury (DILI) in a multiple ascending dose study characterized by dose- and exposure-dependence, delayed onset manifestation, and a high incidence of hepatocellular damage. Retrospective studies investigating the disposition and probable mechanisms of toxicity of BMS-932481 are presented here. These included a mass balance study in bile-duct-cannulated rats and a metabolite profiling study in human hepatocytes, which together demonstrated oxidative metabolism followed by biliary elimination as the primary means of disposition. Additionally, minimal protein covalent binding in hepatocytes and lack of bioactivation products excluded reactive metabolite formation as a probable toxicological mechanism. However, BMS-932481 and 3 major oxidative metabolites were found to inhibit the bile salt export pump (BSEP) and multidrug resistance protein 4 (MRP4) in vitro. Considering human plasma concentrations, the IC50 values against these efflux transporters were clinically meaningful, particularly in the high dose cohort. Active uptake into human hepatocytes in vitro suggested the potential for hepatic levels of BMS-932481 to be elevated further above plasma concentrations, enhancing DILI risk. Conversely, measures of mitochondrial functional decline in hepatocytes treated with BMS-932481 were minimal or modest, suggesting limited contributions to DILI. Collectively, these findings suggested that repeat administration of BMS-932481 likely resulted in high hepatic concentrations of BMS-932481 and its metabolites, which disrupted bile acid transport via BSEP and MRP4, elevating serum biomarkers of liver injury.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide , Enfermedad Hepática Inducida por Sustancias y Drogas , Humanos , Ratas , Animales , Estudios Retrospectivos , Hígado/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hepatocitos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Ácidos y Sales Biliares/metabolismo
7.
Antimicrob Agents Chemother ; 56(10): 5387-96, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22869577

RESUMEN

Asunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, with K(i) values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC(50)s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC(50), 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC(50), >12 µM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposures in vivo in several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC(50)s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.


Asunto(s)
Hepacivirus/efectos de los fármacos , Hepacivirus/patogenicidad , Isoquinolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Línea Celular , Perros , Genotipo , Haplorrinos , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Isoquinolinas/farmacología , Masculino , Ratones , Ratas , Sulfonamidas/farmacología
8.
Cell Rep Methods ; 2(11): 100340, 2022 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-36452860

RESUMEN

Tumor heterogeneity is a major challenge for oncology drug discovery and development. Understanding of the spatial tumor landscape is key to identifying new targets and impactful model systems. Here, we test the utility of spatial transcriptomics (ST) for oncology discovery by profiling 40 tissue sections and 80,024 capture spots across a diverse set of tissue types, sample formats, and RNA capture chemistries. We verify the accuracy and fidelity of ST by leveraging matched pathology analysis, which provides a ground truth for tissue section composition. We then use spatial data to demonstrate the capture of key tumor depth features, identifying hypoxia, necrosis, vasculature, and extracellular matrix variation. We also leverage spatial context to identify relative cell-type locations showing the anti-correlation of tumor and immune cells in syngeneic cancer models. Lastly, we demonstrate target identification approaches in clinical pancreatic adenocarcinoma samples, highlighting tumor intrinsic biomarkers and paracrine signaling.


Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Transcriptoma/genética , Neoplasias Pancreáticas/diagnóstico , Oncología Médica , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genética
9.
J Med Chem ; 65(13): 8948-8960, 2022 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-35704802

RESUMEN

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptores Citoplasmáticos y Nucleares
10.
ACS Med Chem Lett ; 12(9): 1413-1420, 2021 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-34531950

RESUMEN

Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued evaluation.

11.
J Med Chem ; 64(21): 15549-15581, 2021 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-34709814

RESUMEN

The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).


Asunto(s)
Descubrimiento de Drogas , Fibrosis Pulmonar/tratamiento farmacológico , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Fibrosis Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores del Ácido Lisofosfatídico/metabolismo , Relación Estructura-Actividad
12.
J Med Chem ; 63(23): 14740-14760, 2020 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-33226226

RESUMEN

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.


Asunto(s)
Antivirales/farmacología , Péptidos Cíclicos/farmacología , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Antivirales/farmacocinética , Células CHO , Cricetulus , Descubrimiento de Drogas , Estabilidad de Medicamentos , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Estructura Molecular , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/metabolismo , Péptidos Cíclicos/farmacocinética , Ratas , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad
13.
J Med Chem ; 62(2): 831-856, 2019 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-30576602

RESUMEN

3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.


Asunto(s)
Indazoles/química , Indoles/química , Canal de Sodio Activado por Voltaje NAV1.7/química , Neuralgia/tratamiento farmacológico , Sulfonamidas/química , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Células HEK293 , Semivida , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Masculino , Ratones , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuralgia/patología , Técnicas de Placa-Clamp , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/metabolismo
14.
ACS Med Chem Lett ; 9(12): 1217-1222, 2018 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-30613329

RESUMEN

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 → 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.

15.
ACS Med Chem Lett ; 9(2): 143-148, 2018 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-29456803

RESUMEN

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.

16.
ACS Med Chem Lett ; 8(7): 771-774, 2017 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-28740615

RESUMEN

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.

17.
Medchemcomm ; 8(4): 796-806, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-30108798

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.

18.
J Med Chem ; 60(10): 4369-4385, 2017 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-28430437

RESUMEN

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.


Asunto(s)
Antivirales/farmacología , Antivirales/farmacocinética , Benzofuranos/farmacología , Benzofuranos/farmacocinética , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Animales , Antivirales/química , Benzofuranos/química , Perros , Descubrimiento de Drogas , Haplorrinos , Hepatitis C/virología , Humanos , Masculino , Simulación del Acoplamiento Molecular , Ratas , Ratas Sprague-Dawley , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo
19.
J Med Chem ; 59(17): 8042-60, 2016 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-27564532

RESUMEN

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).


Asunto(s)
Antivirales/química , Hepacivirus/efectos de los fármacos , Isoquinolinas/uso terapéutico , Oligopéptidos/química , Sulfonamidas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/administración & dosificación , Antivirales/farmacocinética , Antivirales/farmacología , Perros , Esquema de Medicación , Farmacorresistencia Viral , Hepacivirus/genética , Macaca fascicularis , Masculino , Modelos Moleculares , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Conejos , Ratas Sprague-Dawley , Replicón , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico
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