RESUMEN
Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Dominio Catalítico , Humanos , Modelos Moleculares , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
A potent SARS coronavirus (CoV) 3CL protease inhibitor (TG-0205221, Ki = 53 nM) has been developed. TG-0205221 showed remarkable activity against SARS CoV and human coronavirus (HCoV) 229E replications by reducing the viral titer by 4.7 log (at 5 microM) for SARS CoV and 5.2 log (at 1.25 microM) for HCoV 229E. The crystal structure of TG-0205221 (resolution = 1.93 A) has revealed a unique binding mode comprising a covalent bond, hydrogen bonds, and numerous hydrophobic interactions. Structural comparisons between TG-0205221 and a natural peptide substrate were also discussed. This information may be applied toward the design of other 3CL protease inhibitors.
Asunto(s)
Antivirales/síntesis química , Carbamatos/síntesis química , Cisteína Endopeptidasas/química , Dipéptidos/síntesis química , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Animales , Antivirales/química , Antivirales/farmacología , Carbamatos/química , Carbamatos/farmacología , Línea Celular , Chlorocebus aethiops , Coronavirus Humano 229E/efectos de los fármacos , Proteasas 3C de Coronavirus , Cristalografía por Rayos X , Dipéptidos/química , Dipéptidos/farmacología , Estabilidad de Medicamentos , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Modelos Moleculares , Estructura Molecular , Ratas , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Human coxsackievirus (CV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. In picornavirus, a chymotrypsin-like protease (3C(pro)) is required for viral replication by processing the polyproteins, and thus it is regarded as an antiviral drug target. A 3C-like protease (3CL(pro)) also exists in human coronaviruses (CoV) such as 229E and the one causing severe acute respiratory syndrome (SARS). To combat SARS, we previously had developed peptidomimetic and zinc-coordinating inhibitors of 3CL(pro). As shown in the present study, some of these compounds were also found to be active against 3C(pro) of CV strain B3 (CVB3). Several crystal structures of 3C(pro) from CVB3 and 3CL(pro) from CoV-229E and SARS-CoV in complex with the inhibitors were solved. The zinc-coordinating inhibitor is tetrahedrally coordinated to the His(40)-Cys(147) catalytic dyad of CVB3 3C(pro). The presence of specific binding pockets for the residues of peptidomimetic inhibitors explains the binding specificity. Our results provide a structural basis for inhibitor optimization and development of potential drugs for antiviral therapies.
Asunto(s)
Materiales Biomiméticos/química , Cisteína Endopeptidasas/química , Inhibidores de Cisteína Proteinasa/química , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , Proteínas Virales/química , Zinc/química , Sitios de Unión , Materiales Biomiméticos/uso terapéutico , Proteasas 3C de Coronavirus , Inhibidores de Cisteína Proteinasa/uso terapéutico , Humanos , Estructura Terciaria de Proteína , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/enzimología , Relación Estructura-Actividad , Proteínas Virales/antagonistas & inhibidoresRESUMEN
A structure-activity relationship study was conducted on a series of tetrahydro-beta-carboline-1-carboxylic acid analogs in order to identify the key functionality responsible for activity against the mitogen-activated protein kinase-activated protein kinase 2 enzyme (MK-2). The compounds were further evaluated for their ability to inhibit TNFalpha production in U937 cells and in vivo. These compounds represent a novel structural class of compounds capable of inhibiting MK-2 with remarkable selectivity.
Asunto(s)
Carbolinas/química , Carbolinas/farmacología , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Humanos , Estructura Molecular , Ratas , Relación Estructura-Actividad , Células U937RESUMEN
The first integrally oxidized metal-free phthalocyanine compounds have been synthesized by chemical oxidation. Phthalocyanine (H(2)(pc), pc = phthalocyaninato) was oxidized with IBr to afford the compounds [H(2)(pc)][IBr(2)] (1) and [H(2)(pc)](2)[IBr(2)]BrAC(10)H(7)Br (2), whose structures were determined by means of single-crystal X-ray diffraction methods: [H(2)(pc)][IBr(2)], P2(1)/c, a = 8.0272(9) A, b = 21.258(2) A, c = 18.1439(2) A, beta = 113.975(2) degrees, V = 2828.8(5) A(3), T = 153 K, Z = 4; [H(2)(pc)](2)[IBr(2)]Br.C(10)H(7)Br, P, a = 8.4724(6) A, b = 13.5794(10) A, c = 13.8403(10) A, alpha = 90.854(1) degrees, beta = 103.417(1) degrees, gamma = 97.049(1)E degrees, V = 1535.61(19) A(3), T = 153 K, Z = 1. The extended structure of [H(2)(pc)][IBr(2)] comprises slipped columns of pc rings stacked along the a axis in adjacent columns at approximately 70 degrees to one another. IBr(2-) ions occupy the interstitial columns. The extended structure of [H(2)(pc)](2)[IBr(2)]Br.C(10)H(7)Br comprises slant stacks of pc rings along the crystallographic a axis with IBr(2-) ions, Br(-) ions, and disordered 1-bromonaphthalene molecules in the adjacent, parallel columns. The overall reaction for the formation of 1 is 2H(2)(pc) + 4IBr --> 2[H(2)(pc)][IBr(2)] + I(2), and the overall reaction for the formation of 2 (not including solvent) is 2H(2)(pc) + 3IBr --> [H(2)(pc)](2)Br[IBr(2)] + I(2).