RESUMO
We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay.
Assuntos
Androgênios/química , Androgênios/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores Androgênicos/metabolismo , Anabolizantes/química , Anabolizantes/farmacocinética , Anabolizantes/farmacologia , Androgênios/farmacocinética , Animais , Eunuquismo/tratamento farmacológico , Eunuquismo/metabolismo , Humanos , Masculino , Modelos Moleculares , Músculos/efeitos dos fármacos , Músculos/metabolismo , Nitrilas/farmacocinética , Tamanho do Órgão/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Pirrolidinas/farmacocinética , RatosRESUMO
Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs.
Assuntos
Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Cristalografia por Raios X , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
To develop effective drugs for hypogonadism, sarcopenia, and cachexia, we designed, synthesized, and evaluated selective androgen receptor modulators (SARMs) that exhibit not only anabolic effects on organs such as muscles and the central nervous system (CNS) but also neutral or antagonistic effects on the prostate. Based on the information obtained from a docking model with androgen receptor (AR), we modified a hit compound A identified through high-throughput screening. Among the prepared compounds, 1-(4-cyano-1-naphthyl)-2,3-disubstituted pyrrolidine derivatives 17h, 17m, and 17j had highly potent AR agonistic activities in vitro and good tissue selectivity in vivo. These derivatives increased the weight of the levator ani muscle without influencing the prostate and seminal vesicle. In addition, these compounds induced sexual behavior in castrated rats, indicating that the compounds could also act as agonists on the CNS.
Assuntos
Anabolizantes/síntese química , Androgênios/síntese química , Naftóis/síntese química , Pirrolidinas/síntese química , Receptores Androgênicos/metabolismo , Anabolizantes/farmacologia , Androgênios/farmacologia , Animais , Castração , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Expressão Gênica , Humanos , Masculino , Simulação de Acoplamento Molecular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Naftóis/farmacologia , Próstata/efeitos dos fármacos , Próstata/metabolismo , Ligação Proteica , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/genética , Comportamento Sexual Animal/efeitos dos fármacos , Relação Estrutura-Atividade , Testosterona/farmacologiaRESUMO
A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.
Assuntos
Antagonistas de Receptores de Andrógenos/síntese química , Antineoplásicos/síntese química , Desenho de Fármacos , Pirróis/química , Receptores Androgênicos/química , Substituição de Aminoácidos , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antagonistas de Receptores de Andrógenos/toxicidade , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Mutação , Neoplasias da Próstata/tratamento farmacológico , Pirróis/farmacologia , Pirróis/uso terapêutico , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transplante HeterólogoRESUMO
A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.
Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Imidazóis/farmacologia , Naftalenos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cristalografia por Raios X , Desidroepiandrosterona/sangue , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Humanos , Imidazóis/síntese química , Imidazóis/química , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Masculino , Modelos Moleculares , Simulação de Dinâmica Molecular , Naftalenos/síntese química , Naftalenos/química , Neoplasias da Próstata/sangue , Neoplasias da Próstata/enzimologia , Estereoisomerismo , Relação Estrutura-Atividade , Testosterona/sangueRESUMO
Orteronel (TAK-700) is an investigational, non-steroidal inhibitor of CYP17A1 with preferential inhibition of 17,20-lyase in NCI-H295 cells. Estrogen is synthesized from androgen by aromatase activity, and the effect of orteronel on estrogen synthesis was therefore evaluated. First, it was confirmed that orteronel does not directly inhibit aromatase activity. Second, the specific decline of serum estradiol and androgen levels in hypophysectomized female rats by orteronel in comparison with aromatase inhibitor anastrozole was evaluated; orteronel at doses ≥3mg/kg significantly suppressed serum estradiol, testosterone, androstenedione and 17-hydroxyprogesterone levels, and increased progesterone levels in the estrogen-synthesis pathway. Orteronel, at a dose of 300mg/kg, suppressed serum estradiol concentrations to a similar degree as 0.1mg/kg anastrozole. In contrast, in the corticoid-synthesis pathway, serum aldosterone, corticosterone, and progesterone levels did not change significantly following administration of 300mg/kg of orteronel. Third, the effect of multiple oral administration of orteronel on serum estradiol levels in regularly cycling female cynomolgus monkeys was evaluated. Orteronel at 15mg/kg/day (7.5mg/kg/treatment, twice daily [bid]) continued to suppress the estradiol surge prior to the start of luteal phase for 1.5-times the average duration of three consecutive, pre-treatment menstrual cycles, while serum progesterone was maintained at levels almost equal to those in the luteal phase although a certain portion of this increased level of progesterone could be of adrenal-origin. This suppressive effect on estradiol surge was thought to be reversible since serum estradiol levels started to rise immediately after the discontinuation of orteronel. Estradiol surge was not abrogated by treatment with anastrozole 0.2mg/kg/day (0.1mg/kg/treatment, bid). In summary, orteronel can suppress serum estradiol concentrations in hypophysectomized female rats and monkeys through selective inhibition of CYP17A1 activity, suggesting that orteronel might be effective for hormone-dependent breast cancers and estrogen-dependent diseases.
Assuntos
Estradiol/biossíntese , Estrogênios/biossíntese , Imidazóis/farmacologia , Naftalenos/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Animais , Feminino , Macaca fascicularis , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.
Assuntos
Glândulas Suprarrenais/citologia , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Naftalenos/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroides/sangue , Esteroides/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos , Antagonistas de Androgênios/farmacologia , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Desidroepiandrosterona/antagonistas & inibidores , Desidroepiandrosterona/sangue , Humanos , Hidrocortisona/antagonistas & inibidores , Hidrocortisona/sangue , Imidazóis/sangue , Cetoconazol/farmacologia , Macaca fascicularis , Masculino , Naftalenos/sangue , Orquiectomia , Esteroide 17-alfa-Hidroxilase/metabolismo , Testosterona/antagonistas & inibidores , Testosterona/sangueRESUMO
We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.