RESUMO
Selective androgen receptor modulators (SARMs) are androgens with tissue-selective activity. SARMs that have anabolic activity on muscle while having minimal stimulatory activity on prostate are classified as SARM agonists. They can be used to prevent the loss of lean body mass that is associated with cancer, immunodeficiency, renal disease and aging. They may also have anabolic activity on bone; thus, unlike estrogens, they may reverse the loss of bone strength associated with aging or hypogonadism. Our in-house effort on SARM program discovers a nonsteroidal androgen receptor ligand with a unique imidazolopyrazole moiety in its structure. In vitro, this compound is a weak androgen receptor binder and a weak androgen agonist. Despite this, in orchidectomized mature rats it is an effective SARM agonist, with an ED(50) on levator ani muscle of 3.3mg/kg and an ED(50) on ventral prostate of >30mg/kg. It has its maximal effect on muscle at the dose of 10mg/kg. In addition, this compound has mixed agonistic and antagonistic activities on prostate, reducing the weight of that tissue in intact rats by 22% at 10mg/kg. The compound does not have significant effect on gonadotropin levels or testosterone levels in both orchidectomized and intact male rats. It does not have notable progestin, estrogen or glucocorticoid agonistic or antagonistic activity in rats. In a female sexual behavior model, it improves the sexual desire of ovariectomized female rats for sexually mature intact males over nonsexually ovariectomized females. Overall, the imidazolopyrazole is a potent prostate-sparing candidate for development as a SARM agonist with an appropriate pharmacological profile for clinical benefit in muscle-wasting conditions and female sexual function disorders.
Assuntos
Androgênios/química , Androgênios/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Feminino , Hormônios/sangue , Masculino , Camundongos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Orquiectomia , Ovariectomia , Próstata/efeitos dos fármacos , Próstata/metabolismo , Ratos , Ratos Long-Evans , Comportamento Sexual Animal/efeitos dos fármacosRESUMO
As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
Assuntos
Benzopiranos/química , Benzopiranos/farmacologia , Pós-Menopausa/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Benzopiranos/síntese química , Benzopiranos/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Linhagem Celular Tumoral , Colesterol/sangue , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Fogachos/tratamento farmacológico , Humanos , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Pós-Menopausa/sangue , Ratos , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Relação Estrutura-Atividade , Especificidade por Substrato , Útero/patologia , Vagina/efeitos dos fármacos , Vagina/metabolismoRESUMO
Synthesis of novel 7-pseudo-steroids 1c has been achieved from trenbolone 3 via an efficient 14 step sequence with overall yields of 10-15%. Various substitutions were incorporated at both the aromatic side chain as well as the D ring. The orientation of aromatic side chain at C10 plays a crucial role for progesterone receptor (PR) activity. Compound 2a (T47D=1nM) with -NMe(2) para to the aromatic group along with spirofurane groups in the D ring was the optimal substitution. All compounds were also evaluated for glucocorticoid receptor (GR) antagonist activities in vivo in a rat and found efficacious in uterine complement C3 assay via the oral route of administrations.
Assuntos
Benzoxepinas/síntese química , Receptores de Progesterona/antagonistas & inibidores , Administração Oral , Animais , Benzoxepinas/química , Benzoxepinas/farmacologia , Simulação por Computador , Cristalografia por Raios X , Feminino , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Acetato de Trembolona/químicaRESUMO
A novel series of benzopyran derivatives were synthesized and evaluated as K(ATP) channel openers. Structure-activity relationships were investigated around 4-position of the benzopyran nucleus. Optimization of 4-substituent with some heterocyclic rings led to compound 13b bearing a benzo[d]isoxazol-3-one moiety as a potent and selective K(ATP) channel opener in vitro. In two anesthetized rat models of myogenic bladder overactivity, compound 13b was found to inhibit spontaneous bladder contractions.
Assuntos
Benzopiranos/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/agonistas , Incontinência Urinária de Urgência/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ratos , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiopatologiaRESUMO
Replacement of the 7-CH2 group of natural steroid with an oxygen atom led to identification of unnatural 7-oxa-steroids as potent and selective progesterone receptor antagonists. The unnatural 7-oxa-steroids exhibited a different structure-activity relationship (SAR) from natural steroids. Molecular modeling demonstrated that the switch of carbon to oxygen in the B-ring results in a subtle conformational change of the tetracyclic skeleton and induces a remarkable spatial shift at the terminal end of the side chain of the D-ring. This shift causes the phenyl ring on the D-ring to form a perfect parallel-displaced form of pi-pi interaction with the phenyl ring of Phe794. The unnatural 7-oxa-steroids were orally active in a rat complement C3 assay and showed comparable pharmacokinetic and metabolic profiles to those of the natural steroid, mifepristone.
Assuntos
Esteroides/química , Relação Estrutura-Atividade , Animais , Carbono/química , Complemento C3/química , Simulação por Computador , Concentração Inibidora 50 , Mifepristona/química , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Oxigênio/química , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/antagonistas & inibidoresRESUMO
Androgens are required for the maintenance of normal sexual activity in adulthood and for enhancing muscle growth and lean body mass in adolescents and adults. Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-37654032 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle with ED(50) 0.8 mg/kg, stimulating maximal growth at a dose of 3mg/kg. In contrast, it stimulated ventral prostate growth to 21% of its full size at 3mg/kg. At the same time, JNJ-37654032 reduced prostate weight in intact rats by 47% at 3mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging to monitor body composition, JNJ-37654032 restored about 20% of the lean body mass lost following orchidectomy in aged rats. JNJ-37654032 reduced follicle-stimulating hormone levels in orchidectomized rats and reduced testis size in intact rats. JNJ-37654032 is a potent prostate-sparing SARM with the potential for clinical benefit in muscle-wasting diseases.
Assuntos
Antagonistas de Androgênios/farmacologia , Benzimidazóis/farmacologia , Composição Corporal/efeitos dos fármacos , Magreza/induzido quimicamente , Fatores Etários , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Receptores de Andrógenos , Androgênios , Animais , Benzimidazóis/efeitos adversos , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Masculino , Modelos Biológicos , Orquiectomia , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Testículo/anatomia & histologia , Testículo/efeitos dos fármacosRESUMO
Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-28330835 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle, stimulating maximal growth at a dose of 10 mg/kg. At the same time, JNJ-28330835 reduced prostate weight in intact rats by a mean of 30% at 10 mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging (MRI) to monitor body composition, it prevented half of the loss of lean body mass associated with orchidectomy, and restored about 30% of lost lean mass to aged orchidectomized rats. It had agonist effects on markers of both osteoclast and osteoblast activity, suggesting that it reduces bone turnover. In a model of sexual behavior, JNJ-28330835 enhanced the preference of ovariectomized female rats for sexually intact male rats over nonsexual orchidectomized males. JNJ-28330835 is a prostate-sparing SARM with the potential for clinically beneficial effects in muscle-wasting diseases and sexual function disorders.
Assuntos
Peso Corporal/efeitos dos fármacos , Músculos/efeitos dos fármacos , Próstata/efeitos dos fármacos , Pirazóis/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Feminino , Hormônios/sangue , Hipertrofia/induzido quimicamente , Masculino , Músculos/anatomia & histologia , Tamanho do Órgão/efeitos dos fármacos , Próstata/patologia , Ratos , Ratos Sprague-DawleyRESUMO
A series of novel 11beta-aryl-4',5'-dihydrospiro[estra-4,9-diene-17beta,4'-oxazole] analogs have been evaluated for their antagonist hormonal properties using the T47D cell-based alkaline phosphatase assay and the A549 cell-based functional assay. Some of the compounds showed highly potent, and more selective antiprogestational activity against antiglucocorticoid activity than mifepristone (RU 486).
Assuntos
Oxazóis/síntese química , Oxazóis/farmacologia , Progesterona/antagonistas & inibidores , Linhagem Celular , HumanosRESUMO
A novel series of pyrazolines 2 have been designed, synthesized, and evaluated by in vivo screening as tissue-selective androgen receptor modulators (SARMs). Structure-activity relationships (SAR) were investigated at the R1 to R6 positions as well as the core pyrazoline ring and the anilide linker. Overall, strong electron-withdrawing groups at the R1 and R2 positions and a small group at the R5 and R6 position are optimal for AR agonist activity. The (S)-isomer of 7c exhibits more potent AR agonist activity than the corresponding (R)-isomer. (S)-7c exhibited an overall partial androgenic effect but full anabolic effect via oral administration in castrated rats. It demonstrated a noticeable antiandrogenic effect on prostate in intact rats with endogenous testosterone. Thus, (S)-7c is a tissue-selective nonsteroidal androgen receptor modulator with agonist activity on muscle and mixed agonist and antagonist activity on prostate.
Assuntos
Antagonistas de Receptores de Andrógenos , Androgênios , Pirazóis/síntese química , Anabolizantes/síntese química , Anabolizantes/química , Anabolizantes/farmacologia , Anilidas/síntese química , Anilidas/química , Anilidas/farmacologia , Animais , Cristalografia por Raios X , Desenho de Fármacos , Masculino , Estrutura Molecular , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/efeitos dos fármacos , Orquiectomia , Tamanho do Órgão/efeitos dos fármacos , Diafragma da Pelve , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Testosterona/fisiologiaRESUMO
Through an in vivo screening model, we developed the in vivo SAR of beta-alkylthio indolyl carbinols. Through these efforts we identified a compound with potent oral in vivo efficacy in both immature and mature rat prostate weight reduction models and in a murine xenograft prostate cancer model.
Assuntos
Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Antineoplásicos/síntese química , Química Farmacêutica/métodos , Indóis/síntese química , Metanol/análogos & derivados , Metanol/química , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Modelos Animais de Doenças , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Indóis/farmacologia , Masculino , Camundongos , Transplante de Neoplasias , Ratos , Relação Estrutura-AtividadeRESUMO
Efficient parallel synthesis of novel 7-oxa-steroids 4 has been achieved from the key intermediate 3 via a one-pot four-step sequence. oxa-Steroids 4 with various ortho-, meta-, and para-monosubstituents on the phenyl ring, as well as disubstituted phenyl and heterocycles, were evaluated for progesterone receptor (PR) and glucocorticoid receptor (GR) antagonist activities. SAR study demonstrated that the para-fluorinated substituents on the phenyl ring not only increased the potency for PR in a T47D cell functional assay, but also improved the selectivity over GR in an A549 cell functional assay. The para-fluorophenyl oxa-steroid 4l and the para-trifluoromethylphenyl oxa-steroid 4p were found to be remarkably more potent and more selective PR antagonists than mifepristone, with subnanomolar potency and about 140-fold selectivity over GR. Molecular modeling of the oxa-steroid bound to PR provided meaningful insight for the SAR study. oxa-Steroids 4a and 4b were found to be more efficacious than mifepristone in vivo in a rat uterine complement C3 assay via the oral route, although they were less than or equally potent to mifepristone in the T47D assay.
Assuntos
Química Farmacêutica/métodos , Receptores de Progesterona/antagonistas & inibidores , Esteroides/química , Animais , Linhagem Celular Tumoral , Complemento C3/metabolismo , Desenho de Fármacos , Feminino , Humanos , Mifepristona/farmacologia , Modelos Químicos , Ligação Proteica , Ratos , Receptores de Glucocorticoides/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The synthesis and in vivo SAR of 2-(2,2,2)-trifluoroethyl-benzimidazoles are described. Prostate antagonism and/or levator ani agonism can be modulated by varying the substitution at the 2-position of 5,6-dichloro-benzimidazoles. Potent androgen agonists on the muscle were discovered that strongly bind to the androgen receptor (2-17 nM) and show potent in vivo efficacy (0.03-0.11 mg/day). True SARMs showing both prostate antagonism and levator ani agonism were revealed.
Assuntos
Benzimidazóis/síntese química , Receptores Androgênicos/efeitos dos fármacos , Antagonistas de Receptores de Andrógenos , Androgênios , Animais , Benzimidazóis/agonistas , Benzimidazóis/antagonistas & inibidores , Relação Dose-Resposta a Droga , Indicadores e Reagentes , Masculino , Modelos Moleculares , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: Assess effects of 2 novel selective estrogen receptor modulators on the reproductive system. STUDY DESIGN: Adult, ovariectomized, female Macaca fascicularis, n = 3 per group, orally dosed for 12 weeks with vehicle; selective estrogen receptor modulator 393 (2, 4, or 8 mg/kg/day); selective estrogen receptor modulator 379 (4 mg/kg per day); raloxifene (3 mg/kg per day); tamoxifen (1 mg/kg per day); or ethinyl estradiol (3 microg/kg per day). Outcomes included organ weights, histopathology, plasma lipids, and bone biomarkers. RESULTS: Novel selective estrogen receptor modulators tested did not alter uterine weight or endometrial histology. Tamoxifen and ethinyl estradiol increased uterine weight 2- to 3-fold (P <.05) and endometrial glandular proliferation 5- to 6-fold (P < .05). Adrenal weight was 50% higher in the tamoxifen group. Ethinyl estradiol increased breast lobular epithelial proliferation 6-fold (P < .05). Selective estrogen receptor modulators 393 and ethinyl estradiol decreased bone biomarkers. CONCLUSION: The results for raloxifene, tamoxifen, and ethinyl estradiol are consistent with previous findings, and results for selective estrogen receptor modulator 393 and selective estrogen receptor modulator 379 indicate potential for tissue selectivity.
Assuntos
Estrogênios/farmacologia , Etinilestradiol/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Ovariectomia , Cloridrato de Raloxifeno/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , Útero/efeitos dos fármacos , Vagina/efeitos dos fármacos , Animais , Feminino , Macaca fascicularis , Glândulas Mamárias Animais/patologia , Útero/patologia , Vagina/patologiaRESUMO
Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-diabetic activities. For glucocorticoid receptor (GR) program, we sought an unexplored, synthetically accessible phosphorus-containing steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. One compound 4a, with high oral bioavailability (59%) in rat, exhibited functional antagonism of GR in oral glucose tolerance test (OGTT). Thus this series of compounds might be potentially useful for the treatment of type II diabetes.
Assuntos
Fósforo , Receptores de Glucocorticoides/antagonistas & inibidores , Esteroides/síntese química , Esteroides/farmacocinética , Animais , Disponibilidade Biológica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Teste de Tolerância a Glucose , Humanos , Concentração Inibidora 50 , Mifepristona/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of novel 2-(1H-indol-2-yl)-propan-2-ols have been designed, synthesized, and screened for their ability to inhibit testosterone-induced prostate weight increases in immature rats. Through the use of this paradigm, we were able to identify compounds that exhibited in vivo potency equal to that of the marketed antiandrogen Casodex when orally administered.
Assuntos
Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Indóis/química , Indóis/farmacologia , Próstata/efeitos dos fármacos , Administração Oral , Antagonistas de Androgênios/síntese química , Anilidas/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Indóis/síntese química , Masculino , Nitrilas/farmacologia , Ratos , Relação Estrutura-Atividade , Compostos de Tosil/farmacologiaRESUMO
The synthesis and in vivo SAR of 5,6-dichloro-benzimidazole derivatives as novel selective androgen receptor antagonists are described. During screening of 2-alkyl benzimidazoles, it was found that a trifluoromethyl group greatly enhances antagonist activity in the prostate. Benzimidazole 1 is a potent AR antagonist in the rat prostate (ID50 = 0.15 mg/day).
Assuntos
Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Animais , Indicadores e Reagentes , Masculino , Peso Molecular , Orquiectomia , Próstata/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfetos/síntese química , Sulfonas/síntese químicaRESUMO
A novel imidazolopyrazole derivative has been fortuitously discovered as potent selective androgen receptor modulator with in vivo efficacy.
Assuntos
Pirazóis/síntese química , Pirazóis/farmacologia , Receptores Androgênicos/efeitos dos fármacos , Animais , Ligação Competitiva/efeitos dos fármacos , Cristalografia por Raios X , Técnicas In Vitro , Indicadores e Reagentes , Ligantes , Masculino , Modelos Moleculares , Músculo Esquelético/efeitos dos fármacos , Orquiectomia , Tamanho do Órgão , Próstata/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Testosterona/metabolismoRESUMO
The pharmacological activity of JNJ-26146900 is described. JNJ-26146900 is a nonsteroidal androgen receptor (AR) ligand with tissue-selective activity in rats. The compound was evaluated in in vitro and in vivo models of AR activity. It binds to the rat AR with a K(i) of 400nM and acts as a pure androgen antagonist in an in vitro cell-based assay. Its in vitro profile is similar to the androgen antagonist bicalutamide (Casodex). In intact rats, JNJ-26146900 reduces ventral prostate weight with an oral potency (ED(50)) of 20-30mg/kg, again comparable to that of bicalutamide. JNJ-26146900 prevented prostate tumor growth in the Dunning rat model, maximally inhibiting growth at a dose of 10mg/kg. It slowed tumor growth significantly in a CWR22-LD1 mouse xenograft model of human prostate cancer. It was tested in aged male rats for its ability to prevent bone loss and loss of lean body mass following orchidectomy. After 6 weeks of dosing, bone volume decreased by 33% in orchidectomized versus intact vehicle-treated rats with a probability (P) of less than 0.05, as measured by micro-computerized tomography analysis. At a dose of 30mg/kg, JNJ-26146900 significantly reduced castration-induced tibial bone loss as indicated by the following parameters: bone volume, trabecular connectivity, trabecular number and spacing between trabeculae. Bone mineral density decreased from 229+/-34mg/cm(3) of hydroxyapatite to 166+/-26mg/cm(3) following orchidectomy, and was maintained at 194+/-20mg/cm(3) with JNJ-26146900 treatment (P<0.05 relative to orchidectomy alone). Using magnetic resonance imaging, the compound was found to partially prevent orchidectomy-induced loss of lean body mass. Our data show that selective androgen receptor modulators (SARMs) have the potential for anabolic effects on bone and muscle while maintaining therapeutic efficacy in prostate cancer.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antagonistas de Receptores de Andrógenos , Osso e Ossos/patologia , Indóis/farmacologia , Orquiectomia/efeitos adversos , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Animais , Composição Corporal , Densidade Óssea/efeitos dos fármacos , Células COS , Chlorocebus aethiops , Modelos Animais de Doenças , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-DawleyRESUMO
The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID(50)=0.13mg/day), compared with bicalutamide (ID(50)=0.23mg/day).
Assuntos
Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Antineoplásicos Hormonais/síntese química , Antineoplásicos Hormonais/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Alquilação , Anilidas/farmacologia , Animais , Indicadores e Reagentes , Masculino , Nitrilas/farmacologia , Orquiectomia , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Compostos de Tosil/farmacologiaRESUMO
A novel series of oxa-steroids 6 derived from (8S, 13S, 14R)-7-oxa-estra-4,9-diene-3,17-dione 1 have been synthesized and identified as potent and selective progesterone receptor antagonists. These novel oxa-steroids showed similar potency to mifepristone. Preliminary SAR study resulted in the most potent 17-phenylethynyl oxa-steroid 6i wih an IC(50) of 1.4nM. In contrast to the equipotent mifepristone toward the progesterone receptor (PR) and glucocorticoid receptor (GR), compound 6i had over 200-fold selectivity for PR over GR.