RESUMEN
Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A central hallmark of tumorigenesis is metabolic alterations that increase mitochondrial reactive oxygen species (mROS). In response, cancer cells upregulate their antioxidant capacity and redox-responsive signaling pathways. A promising chemotherapeutic approach is to increase ROS to levels incompatible with tumor cell survival. Mitochondrial peroxiredoxin 3 (PRX3) plays a significant role in detoxifying hydrogen peroxide (H2O2). PRX3 is a molecular target of thiostrepton (TS), a natural product and FDA-approved antibiotic. TS inactivates PRX3 by covalently adducting its two catalytic cysteine residues and crosslinking the homodimer. Using cellular models of malignant mesothelioma, we show here that PRX3 expression and mROS levels in cells correlate with sensitivity to TS and that TS reacts selectively with PRX3 relative to other PRX isoforms. Using recombinant PRXs 1-5, we demonstrate that TS preferentially reacts with a reduced thiolate in the PRX3 dimer at mitochondrial pH. We also show that partially oxidized PRX3 fully dissociates to dimers, while partially oxidized PRX1 and PRX2 remain largely decameric. The ability of TS to react with engineered dimers of PRX1 and PRX2 at mitochondrial pH, but inefficiently with wild-type decameric protein at cytoplasmic pH, supports a novel mechanism of action and explains the specificity of TS for PRX3. Thus, the unique structure and propensity of PRX3 to form dimers contribute to its increased sensitivity to TS-mediated inactivation, making PRX3 a promising target for prooxidant cancer therapy.
RESUMEN
Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.
Asunto(s)
ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Amidas/química , Aminoquinolinas/química , NAD/metabolismo , Quinolinas/química , Amidas/síntesis química , Amidas/farmacología , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacología , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Humanos , Hidrólisis , Hígado/metabolismo , Membranas Artificiales , Ratones Endogámicos C57BL , Modelos Moleculares , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Permeabilidad , Conformación Proteica , Quinolinas/síntesis química , Quinolinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.
Asunto(s)
ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Quinolonas/química , Quinolonas/farmacología , Tiazoles/química , Tiazoles/farmacología , ADP-Ribosil Ciclasa 1/metabolismo , Animales , Línea Celular , Perros , Descubrimiento de Drogas , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Músculos/efectos de los fármacos , Músculos/metabolismo , NAD/análisis , NAD/sangre , NAD/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Quinolonas/síntesis química , Quinolonas/farmacocinética , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Oxazolidinonas/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Evaluación Preclínica de Medicamentos , Transferencia Resonante de Energía de Fluorescencia , Humanos , Modelos Moleculares , Estructura Molecular , Oxazolidinonas/química , Relación Estructura-ActividadRESUMEN
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Quinolinas/química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Sitios de Unión , Glucemia/metabolismo , Cristalografía por Rayos X , Diabetes Mellitus Experimental/metabolismo , Perros , Transferencia Resonante de Energía de Fluorescencia , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ligandos , Ratones , Conformación Molecular , Estructura Terciaria de Proteína , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
A novel series of potent substituted anilinoquinolines were discovered as c-fms inhibitors. The potency could be manipulated upon modification of the C4 aniline and C7 aryl functionality. Pharmacokinetic analysis identified a metabolically stable analog suitable for further investigative work.
Asunto(s)
Compuestos de Anilina/química , Quinolinas/síntesis química , Quinolinas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Sitios de Unión , Línea Celular , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Concentración 50 Inhibidora , Modelos Animales , Modelos Moleculares , Estructura Molecular , Quinolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A set of novel heterocyclic pyrimidyl hydrazones has been synthesized as inhibitors of glycogen synthase kinase-3 (GSK-3) with the most active exhibiting low nanomolar activity. Quantum mechanical calculations indicate that of the conformational factors that could determine binding affinity, the planarity of the phenyl ring in relation to the central core and the conformation of the hydrazone chain may be the most influential.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Hidrazinas/síntesis química , Hidrazinas/farmacología , Concentración 50 Inhibidora , Modelos Químicos , EstereoisomerismoRESUMEN
The first report on the identification and structure-activity relationships of a novel series of GPR40 agonists based on a 3-(4-{[N-alkyl]amino}phenyl)propanoic acid template is described. Structural modifications to the original screening hit yielded compounds with a 100-fold increase in potency at the human GPR40 receptor and pEC(50)s in the low nanomolar range. The carboxylic acid moiety is not critical for activity but typically elicits an agonistic response higher than those observed with carboxamide replacements. These compounds may prove useful in unraveling the therapeutic potential of this receptor for the treatment of Type 2 diabetes.