RESUMEN
Inhibition of inducible T-cell kinase (ITK), a nonreceptor tyrosine kinase, may represent a novel treatment for allergic asthma. In our previous reports, we described the discovery of sulfonylpyridine (SAP), benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI) series as novel ITK inhibitors and how computational tools such as dihedral scans and docking were used to support this process. X-ray crystallography and modeling were applied to provide essential insight into ITK-ligand interactions. However, "visual inspection" traditionally used for the rationalization of protein-ligand affinity cannot always explain the full complexity of the molecular interactions. The fragment molecular orbital (FMO) quantum-mechanical (QM) method provides a complete list of the interactions formed between the ligand and protein that are often omitted from traditional structure-based descriptions. FMO methodology was successfully used as part of a rational structure-based drug design effort to improve the ITK potency of high-throughput screening hits, ultimately delivering ligands with potency in the subnanomolar range.
Asunto(s)
Interleucina-2/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Benzotiazoles/química , Cristalografía por Rayos X , Diseño de Fármacos , Inducción Enzimática , Indazoles/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/biosíntesis , Piridinas/química , Teoría CuánticaRESUMEN
Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/química , Sitios de Unión , Cristalografía por Rayos X , Cinética , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/metabolismo , Pirazoles/química , Piridinas/síntesis química , Piridinas/metabolismo , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.
Asunto(s)
Indazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Células Jurkat , Cinética , Ratones , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.
Asunto(s)
Benzotiazoles/química , Benzotiazoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Benzotiazoles/síntesis química , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Ratones , Modelos Moleculares , Proteínas Tirosina Quinasas/química , Transducción de Señal , Relación Estructura-ActividadRESUMEN
A family of biaryl substituted 1,4-diaminocyclohexanamides of 3-chlorobenzothiophene-2-carboxylic acid is reported as picomolar modulators of Hedgehog protein function. SAR for the 1,4-diaminocyclohexane group is shown to be exquisitely sensitive to substitution on the 4-amino group, and SAR for the 3-chlorobenzothiophene group is highly specific. Preliminary SAR studies of the biaryl substituent led to a picomolar compound with in vivo activity.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Química Farmacéutica/métodos , Proteínas Hedgehog/agonistas , Administración Oral , Animales , Ácidos Carboxílicos/farmacología , Línea Celular , Diseño de Fármacos , Proteínas Hedgehog/metabolismo , Humanos , Ratones , Modelos Biológicos , Modelos Químicos , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.
Asunto(s)
Antivirales/síntesis química , Azoles/síntesis química , Benzotiadiazinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Hepatitis C/tratamiento farmacológico , Piridinas/síntesis química , Pirimidinas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacología , Azoles/farmacología , Benzotiadiazinas/farmacología , Química Farmacéutica/métodos , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Hepacivirus/metabolismo , Técnicas In Vitro , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Químicos , Estructura Molecular , Piridinas/farmacología , Pirimidinas/farmacología , Relación Estructura-Actividad , Proteínas no Estructurales Virales/químicaRESUMEN
[reaction: see text] A synthesis of 28, the carbon framework of the eleutherobin aglycone, is reported in a 15-step sequence from readily available starting materials. The tandem Diels-Alder reaction of 6 and 7 to produce 18, in which three new rings and six new stereocenters are formed, is a key step in the reaction sequence.
Asunto(s)
Alcaloides/síntesis química , Antineoplásicos/síntesis química , Diterpenos , Antozoos/química , Ciclización , Indicadores y Reactivos , Conformación MolecularRESUMEN
An Mg2+ and ATP dependent beta-lactam synthetase (BLS) catalyses formation of a beta-lactam ring during the biosynthesis of clavulanic acid, an important beta-lactamase inhibitor. An epimeric mixture of a 2-methylated derivative of the natural BLS substrate N2-(2-carboxyethyl)-L-arginine was synthesised and found to be a substrate for the enzyme. The epimeric products were characterised by 1H NMR and mass spectrometric analyses. The results suggest that a modified version of BLS might be used to catalyse the preparation of intermediates useful for the synthesis of beta-lactam antibiotics.