RESUMEN
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
Recently, a new class of HIV reverse transcriptase (HIV-RT) inhibitors has been reported. The novel mechanism of inhibition by this class involves competitive binding to the active site of the RT enzyme and has been termed Nucleotide-Competing Reverse Transcriptase Inhibitors (NcRTIs). In this publication we describe the optimization of a novel benzofurano[3,2-d]pyrimidin-2-one series of NcRTIs. The starting point for the current study was inhibitor 2, which had high biochemical and antiviral potency but only moderate permeability in a Caco-2 assay and high B-to-A efflux, resulting in moderate rat bioavailability and low Cmax. We present herein the results and strategies we employed to optimize both the potency as well as the permeability, metabolic stability and pharmacokinetic profile of this series. One of the key observations of the present study was the importance of shielding polar functionality, at least in the context of the current chemotype, to enhance permeability. These studies led to the identification of inhibitors 39 and 45, which display sub-nanomolar antiviral potency in a p24 ELISA assay with significantly reduced efflux ratios (ratios <1.5). These inhibitors also display excellent rat pharmacokinetic profiles with high bioavailabilities and low clearance.
Asunto(s)
Antivirales/farmacología , Benzofuranos/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH/efectos de los fármacos , Pirimidinonas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Administración Oral , Animales , Antivirales/administración & dosificación , Antivirales/química , Benzofuranos/química , Disponibilidad Biológica , Células CACO-2 , Relación Dosis-Respuesta a Droga , Transcriptasa Inversa del VIH/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Pirimidinonas/administración & dosificación , Pirimidinonas/química , Ratas , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-ActividadRESUMEN
A HTS screen led to the identification of a benzofurano[3,2-d]pyrimidin-2-one core structure which upon further optimization resulted in 1 as a potent HIV-1 nucleotide competing reverse transcriptase inhibitor (NcRTI). Investigation of the SAR at N-1 allowed significant improvements in potency and when combined with the incorporation of heterocycles at C-8 resulted in potent analogues not requiring a basic amine to achieve antiviral activity. Additional modifications at N-1 resulted in 33 which demonstrated excellent antiviral potency and improved physicochemical properties.
Asunto(s)
Benzofuranos/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Nucleótidos/química , Pirimidinonas/química , Inhibidores de la Transcriptasa Inversa/química , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Microsomas Hepáticos/metabolismo , Nucleótidos/metabolismo , Unión Proteica , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors.
Asunto(s)
Benzofuranos/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Nucleótidos/química , Pirimidinonas/química , Inhibidores de la Transcriptasa Inversa/química , Animales , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Microsomas Hepáticos/metabolismo , Nucleótidos/metabolismo , Unión Proteica , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Ratas , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
A key directed remote metalation (DreM)-carbamoyl migration strategy was applied in an efficient synthesis of the naturally occurring 6H-naphtho[1,2-b]benzopyran-6-one defucogilvocarcin V (1a, Scheme 11). The required biarylcarbamate 33d was best prepared by a high yielding Suzuki coupling reaction of 31a with the differentially protected trioxygenated naphthalene coupling partner 32d which was synthesized using a selective acylation of a juglone derivative. In the late stages of the synthesis, the triflate 39 served as the common intermediate to install the required C-8 vinyl group of 1a (Stille coupling) as well as the required substituents for the preparation of defucogilvocarcins M (1b) and E (1c). A variety of protecting group strategies were investigated and provided insight into which groups are preferred for the DreM-carbamoyl migration process. The strategic lessons learned from this total synthesis were applied in the successful total synthesis of the structurally similar natural product arnottin I (2).
Asunto(s)
Cumarinas/síntesis química , Benzopiranos/síntesis química , Productos Biológicos/síntesis química , Catálisis , Glicósidos , Elementos de TransiciónRESUMEN
A concise synthesis of heteroaryl dibenzopyranones 9a,b, 10a,b, 11a-c, and 12a-c has been achieved by the LDA-induced migration of heterobiaryl O-carbamates 18, 21, 25, and 30 which, in turn, were prepared in good yield using a combined directed ortho lithiation (DoM)-transition-metal-catalyzed Suzuki cross-coupling strategy. An efficient and general route to a wide variety of heterocycles including coumestans 19a,c and the previously unknown isothiocoumestan ring system 22b has been thereby achieved.
Asunto(s)
Benzopiranos/síntesis química , Carbamatos/química , Cumarinas/síntesis química , Compuestos Heterocíclicos/síntesis química , Metales/química , Fenómenos Químicos OrgánicosRESUMEN
[structure: see text] The protected hydroxyethylene dipeptide isostere of Gln-Arg and the tripeptide derivative 1 were synthesized as components of potential peptidase inhibitors.
Asunto(s)
Arginina/química , Etilenos/química , Glutamina/química , Oligopéptidos/síntesis química , Dipéptidos/química , Lactonas/química , Estructura Molecular , Oligopéptidos/química , EstereoisomerismoRESUMEN
2-arylamino-4-trifluoromethyl-5-aminomethylthiazoles represent a novel series of high-affinity corticotropin releasing factor-1 receptor (CRF(1)R) antagonists that are prepared in three steps in good overall yields. Herein, we report binding SAR as well as anxiolytic activity of an exemplary compound (7a, K(i)=8.6 nM) in a mouse canopy model.