RESUMEN
Androgen replacement therapy is a promising strategy for the treatment of frailty; however, androgens pose risks for unwanted effects including virilization and hypertrophy of reproductive organs. Selective Androgen Receptor Modulators (SARMs) retain the anabolic properties of androgens in bone and muscle while having reduced effects in other tissues. We describe two structurally similar 4-aza-steroidal androgen receptor (AR) ligands, Cl-4AS-1, a full agonist, and TFM-4AS-1, which is a SARM. TFM-4AS-1 is a potent AR ligand (IC(50), 38 nm) that partially activates an AR-dependent MMTV promoter (55% of maximal response) while antagonizing the N-terminal/C-terminal interaction within AR that is required for full receptor activation. Microarray analyses of MDA-MB-453 cells show that whereas Cl-4AS-1 behaves like 5alpha-dihydrotestosterone (DHT), TFM-4AS-1 acts as a gene-selective agonist, inducing some genes as effectively as DHT and others to a lesser extent or not at all. This gene-selective agonism manifests as tissue-selectivity: in ovariectomized rats, Cl-4AS-1 mimics DHT while TFM-4AS-1 promotes the accrual of bone and muscle mass while having reduced effects on reproductive organs and sebaceous glands. Moreover, TFM-4AS-1 does not promote prostate growth and antagonizes DHT in seminal vesicles. To confirm that the biochemical properties of TFM-4AS-1 confer tissue selectivity, we identified a structurally unrelated compound, FTBU-1, with partial agonist activity coupled with antagonism of the N-terminal/C-terminal interaction and found that it also behaves as a SARM. TFM-4AS-1 and FTBU-1 represent two new classes of SARMs and will allow for comparative studies aimed at understanding the biophysical and physiological basis of tissue-selective effects of nuclear receptor ligands.
Asunto(s)
Anabolizantes/farmacocinética , Andrógenos , Congéneres de la Testosterona/farmacología , Anabolizantes/química , Animales , Antígenos Virales de Tumores/metabolismo , Masculino , Regiones Promotoras Genéticas , Próstata/crecimiento & desarrollo , Próstata/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/metabolismo , Congéneres de la Testosterona/química , Proteínas del Núcleo Viral/metabolismoRESUMEN
The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.
Asunto(s)
Benzofuranos/síntesis química , Ácidos Carboxílicos/síntesis química , Hipolipemiantes/síntesis química , PPAR alfa/agonistas , Animales , Benzofuranos/química , Benzofuranos/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Colesterol/sangre , Cricetinae , Perros , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/química , Hipolipemiantes/farmacología , Técnicas In Vitro , Masculino , Mesocricetus , Conformación Molecular , PPAR alfa/genética , Ensayo de Unión Radioligante , Estereoisomerismo , Relación Estructura-Actividad , Activación Transcripcional , Triglicéridos/sangreRESUMEN
Patients with type 2 diabetes mellitus exhibit hyperglycemia and dyslipidemia as well as a markedly increased incidence of atherosclerotic cardiovascular disease. Here we report the characterization of a novel arylthiazolidinedione capable of lowering both glucose and lipid levels in animal models. This compound, designated TZD18, is a potent agonist with dual human peroxisome proliferator-activated receptor (PPAR)-alpha/gamma activities. In keeping with its PPARgamma activity, TZD18 caused complete normalization of the elevated glucose in db/db mice and Zucker diabetic fatty rats. TZD18 lowered both cholesterol and triglycerides in hamsters and dogs. TZD18 inhibited cholesterol biosynthesis at steps before mevalonate and reduced hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Moreover, TZD18 significantly suppressed gene expression of fatty acid synthesis and induced expression of genes for fatty acid degradation and triglyceride clearance. Studies on 17 additional PPARalpha or PPARalpha/gamma agonists showed that lipid lowering in hamsters correlated with the magnitude of hepatic gene expression changes. Importantly, the presence of PPARgamma agonism did not affect the relationship between hepatic gene expression and lipid lowering. Taken together, these data suggest that PPARalpha/gamma agonists, such as TZD18, affect lipid homeostasis, leading to an antiatherogenic plasma lipid profile. Agents with these properties may provide favorable means for treatment of type 2 diabetes and dyslipidemia and the prevention of atherosclerotic cardiovascular disease.
Asunto(s)
Homeostasis/efectos de los fármacos , Hipolipemiantes/farmacología , Metabolismo de los Lípidos , Éteres Fenílicos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas/farmacología , Factores de Transcripción/agonistas , Animales , Glucemia/metabolismo , Células COS , Colesterol/biosíntesis , Colesterol/sangre , Cricetinae , Diabetes Mellitus/sangre , Perros , Expresión Génica/efectos de los fármacos , Humanos , Hidroximetilglutaril-CoA Reductasas/efectos de los fármacos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Lípidos/sangre , Hígado/metabolismo , Masculino , Mesocricetus , Ratones , Obesidad/sangre , Éteres Fenílicos/química , ARN Mensajero/metabolismo , Ratas , Ratas Zucker , Tiazolidinedionas/química , Triglicéridos/antagonistas & inhibidores , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model.
Asunto(s)
Benzopiranos/síntesis química , Cromanos/síntesis química , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Éteres Fenílicos/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Animales , Benzopiranos/química , Benzopiranos/farmacocinética , Benzopiranos/farmacología , Cromanos/química , Cromanos/farmacocinética , Cromanos/farmacología , Cricetinae , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Perros , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Macaca mulatta , Masculino , Mesocricetus , Ratones , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Éteres Fenílicos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Transactivadores/síntesis química , Transactivadores/química , Transactivadores/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Beginning with a moderately potent PPARgamma agonist 9, a series of potent and highly subtype-selective PPARalpha agonists was identified through a systematic SAR study. Based on the results of the efficacy studies in the hamster and dog models of dyslipidemia and the desired pharmacokinetic data, the optimized compound 39 was selected for further profiling.
Asunto(s)
Diseño de Fármacos , Dislipidemias/tratamiento farmacológico , Hipolipemiantes/síntesis química , PPAR alfa/agonistas , Animales , Cricetinae , Perros , Haplorrinos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Estructura Molecular , PPAR alfa/genética , Ratas , Relación Estructura-Actividad , Activación TranscripcionalRESUMEN
A SAR study was conducted on chromane-2-carboxylic acid toward selective PPARalpha agonisim. As a result, highly potent, and selective PPARalpha agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models.
Asunto(s)
Ácidos Carboxílicos/farmacología , Cromanos/farmacología , Hipolipemiantes/farmacología , PPAR alfa/agonistas , Animales , Ácidos Carboxílicos/administración & dosificación , Ácidos Carboxílicos/síntesis química , Cromanos/administración & dosificación , Cromanos/síntesis química , Cricetinae , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Hipolipemiantes/administración & dosificación , Hipolipemiantes/síntesis química , Macaca mulatta , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARalpha/gamma agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
Asunto(s)
Hipoglucemiantes/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas/síntesis química , Factores de Transcripción/agonistas , Administración Oral , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Hiperglucemia/tratamiento farmacológico , Hipertrigliceridemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Ratones , Receptores Citoplasmáticos y Nucleares/metabolismo , Rosiglitazona , Relación Estructura-Actividad , Tiazolidinedionas/farmacología , Factores de Transcripción/metabolismoRESUMEN
Beginning with the weakly active lead structure 1, a new series of hPPAR agonists was developed. In vivo glucose and triglyceride lowering activity was obtained by homologation and oxamination to 3, then conversion to substituted benzisoxazoles 4 and 5. Further manipulation afforded benzofurans 6 and 7. Compound 7 was of comparable potency as a glucose and triglyceride lowering agent in insulin resistant rodents to BRL 49653.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Fenilacetatos/síntesis química , Fenilacetatos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas , Factores de Transcripción/agonistas , Animales , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Hipoglucemiantes/farmacocinética , Resistencia a la Insulina , Masculino , Ratones , Fenilacetatos/farmacocinética , Ratas , Ratas Zucker , Rosiglitazona , Tiazoles/farmacología , Triglicéridos/sangreRESUMEN
A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual alpha/gamma agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.
Asunto(s)
Hipoglucemiantes/farmacología , Oxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Administración Oral , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Oxazoles/química , Oxazoles/farmacocinética , Relación Estructura-ActividadRESUMEN
A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.