RESUMO
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.
Assuntos
Anabolizantes/farmacocinética , Androgênios , Congêneres da Testosterona/farmacologia , Anabolizantes/química , Animais , Antígenos Virais de Tumores/metabolismo , Masculino , Regiões Promotoras Genéticas , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Congêneres da Testosterona/química , Proteínas do Core Viral/metabolismoRESUMO
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.
Assuntos
Benzofuranos/síntese química , Ácidos Carboxílicos/síntese química , Hipolipemiantes/síntese química , PPAR alfa/agonistas , Animais , Benzofuranos/química , Benzofuranos/farmacologia , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Colesterol/sangue , Cricetinae , Cães , Humanos , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Técnicas In Vitro , Masculino , Mesocricetus , Conformação Molecular , PPAR alfa/genética , Ensaio Radioligante , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional , Triglicerídeos/sangueRESUMO
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.
Assuntos
Homeostase/efeitos dos fármacos , Hipolipemiantes/farmacologia , Metabolismo dos Lipídeos , Éteres Fenílicos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas/farmacologia , Fatores de Transcrição/agonistas , Animais , Glicemia/metabolismo , Células COS , Colesterol/biossíntese , Colesterol/sangue , Cricetinae , Diabetes Mellitus/sangue , Cães , Expressão Gênica/efeitos dos fármacos , Humanos , Hidroximetilglutaril-CoA Redutases/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/metabolismo , Lipídeos/sangue , Fígado/metabolismo , Masculino , Mesocricetus , Camundongos , Obesidade/sangue , Éteres Fenílicos/química , RNA Mensageiro/metabolismo , Ratos , Ratos Zucker , Tiazolidinedionas/química , Triglicerídeos/antagonistas & inibidores , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
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.
Assuntos
Benzopiranos/síntese química , Cromanos/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Éteres Fenílicos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Benzopiranos/química , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Cromanos/química , Cromanos/farmacocinética , Cromanos/farmacologia , Cricetinae , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Cães , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Macaca mulatta , Masculino , Mesocricetus , Camundongos , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Éteres Fenílicos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Transativadores/síntese química , Transativadores/química , Transativadores/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Hipolipemiantes/síntese química , PPAR alfa/agonistas , Animais , Cricetinae , Cães , Haplorrinos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Estrutura Molecular , PPAR alfa/genética , Ratos , Relação Estrutura-Atividade , Ativação TranscricionalRESUMO
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.
Assuntos
Ácidos Carboxílicos/farmacologia , Cromanos/farmacologia , Hipolipemiantes/farmacologia , PPAR alfa/agonistas , Animais , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/síntese química , Cromanos/administração & dosagem , Cromanos/síntese química , Cricetinae , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/síntese química , Macaca mulatta , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Hipoglicemiantes/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas/síntese química , Fatores de Transcrição/agonistas , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Hiperglicemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Camundongos , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Fenilacetatos/síntese química , Fenilacetatos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas , Fatores de Transcrição/agonistas , Animais , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Hipoglicemiantes/farmacocinética , Resistência à Insulina , Masculino , Camundongos , Fenilacetatos/farmacocinética , Ratos , Ratos Zucker , Rosiglitazona , Tiazóis/farmacologia , Triglicerídeos/sangueRESUMO
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.
Assuntos
Hipoglicemiantes/farmacologia , Oxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Administração Oral , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Oxazóis/química , Oxazóis/farmacocinética , Relação Estrutura-AtividadeRESUMO
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.