RESUMEN
The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450/farmacocinética , Diseño de Fármacos , Piperazinas/farmacocinética , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Estilbenos/farmacocinética , Animales , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Cobayas , Semivida , Microsomas Hepáticos/metabolismo , Piperazinas/síntesis química , Piperazinas/química , Estereoisomerismo , Estilbenos/síntesis química , Estilbenos/química , Relación Estructura-ActividadRESUMEN
Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) plays an important role in triglyceride synthesis and is a target of interest for the treatment of metabolic disorders. Herein we describe the structure-activity relationship of a novel tetralone series of DGAT1 inhibitors and our strategies for overcoming genotoxic liability of the anilines embedded in the chemical structures, leading to the discovery of a candidate compound, (S)-2-(6-(5-(3-(3,4-difluorophenyl)ureido)pyrazin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid (GSK2973980A, 26d). Compound 26d is a potent and selective DGAT1 inhibitor with excellent DMPK profiles and in vivo efficacy in a postprandial lipid excursion model in mice. Based on the overall biological and developability profiles and acceptable safety profiles in the 7-day toxicity studies in rats and dogs, compound 26d was selected as a candidate compound for further development in the treatment of metabolic disorders.
RESUMEN
Metabolic Syndrome, also referred to as 'Syndrome X' or 'Insulin Resistance Syndrome,' remains a major, unmet medical need despite over 30years of intense effort. Recent research suggests that there may be a causal link between this condition and abnormal glucocorticoid processing. Specifically, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis leads to increased systemic cortisol concentrations. Cushing' syndrome, a disorder that is also typified by a marked elevation in levels of cortisol, produces clinical symptomology that is similar to those observed in MetS, and they can be alleviated by decreasing circulating cortisol concentrations. As a result, it has been suggested that decreasing systemic cortisol concentration might have a positive impact on the progression of MetS. This could be accomplished through inhibition of enzymes in the cortisol synthetic pathway, 11ß-hydroxylase (Cyp11B1), 17α-hydroxylase-C17,20-lyase (Cyp17), and 21-hydroxylase (Cyp21). We have identified a series of novel sulfonamide analogs of (2S,4R)-Ketoconazole that are potent inhibitors of these enzymes. In addition, selected members of this class of compounds have pharmacokinetic properties consistent with orally delivered drugs, making them well suited to further investigation as potential therapies for MetS.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450/química , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Cetoconazol/análogos & derivados , Cetoconazol/farmacología , Síndrome Metabólico/tratamiento farmacológico , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Inhibidores Enzimáticos del Citocromo P-450/farmacocinética , Diseño de Fármacos , Femenino , Cobayas , Humanos , Cetoconazol/farmacocinética , Masculino , Síndrome Metabólico/enzimología , Sulfonamidas/farmacocinéticaRESUMEN
We present a novel series of selective androgen receptor modulators (SARMs) which shows excellent biological activity and physical properties. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitriles showed potent binding to the androgen receptor (AR) and activated AR-mediated transcription in vitro. Representative compounds demonstrated diminished activity in promoting the intramolecular interaction between the AR carboxyl (C) and amino (N) termini. This N/C-termini interaction is a biomarker assay for the undesired androgenic responses in vivo. In orchidectomized rats, daily administration of a lead compound from this series showed anabolic activity by increasing levator ani muscle weight. Importantly, minimal androgenic effects (increased tissue weights) were observed in the prostate and seminal vesicles, along with minimal repression of circulating luteinizing hormone (LH) levels and no change in the lipid and triglyceride levels. This lead compound completed a two week rat toxicology study, and was well tolerated at doses up to 100 mg/kg/day, the highest dose tested, for 14 consecutive days.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Receptores Androgénicos/efectos de los fármacos , Anabolizantes/síntesis química , Anabolizantes/farmacología , Animales , Área Bajo la Curva , Disponibilidad Biológica , Biomarcadores , Línea Celular , Metabolismo de los Lípidos/efectos de los fármacos , Hormona Luteinizante/antagonistas & inhibidores , Hormona Luteinizante/metabolismo , Masculino , Modelos Moleculares , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/crecimiento & desarrollo , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad , Testículo/efectos de los fármacos , Testículo/metabolismo , Testosterona/biosíntesis , Triglicéridos/metabolismo , Difracción de Rayos XRESUMEN
An elegant reagent-controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. Inâ silico studies were used to estimate the drug-like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14.
Asunto(s)
Antibacterianos/síntesis química , Antineoplásicos/síntesis química , Compuestos Heterocíclicos/síntesis química , Lactamas Macrocíclicas/química , Compuestos de Espiro/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclización , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Metilación , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Peso Molecular , Compuestos de Espiro/química , Compuestos de Espiro/farmacologíaRESUMEN
Analogs of the anti-tumor agent camptothecin with both closed E-rings (lactone and ether) and open E-rings (reduced acid, hydrazide, and protected Weinreb amide) have been prepared and tested in topoisomerase and cellular assays. The results provide insights into the structural features of the camptothecin E-ring that affect biological activity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/síntesis química , Camptotecina/farmacología , Antineoplásicos/química , Bioensayo , Camptotecina/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de TopoisomerasaRESUMEN
Both enantiomers of 20-fluorocamptothecin and the racemate have been prepared by total synthesis. The (R)-enantiomer is essentially inactive in a topoisomerase-I/DNA assay, while the (S)-enantiomer is much less active than (20S)-camptothecin. The lactone ring of 20-fluorocamptothecin hydrolyzes more rapidly than that of camptothecin in PBS. The results provide insight into the role of the 20-hydroxy group in the binding of camptothecin to topoisomerase-I and DNA.