RESUMO
Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.
Assuntos
Antineoplásicos/farmacologia , Cinamatos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indazóis/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Indazóis/síntese química , Indazóis/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Estrutura Molecular , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-Atividade , Tamoxifeno/síntese química , Tamoxifeno/químicaRESUMO
Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antagonistas do Receptor de Estrogênio/uso terapêutico , Indazóis/uso terapêutico , Tamoxifeno/uso terapêutico , Animais , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Cinamatos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Antagonistas do Receptor de Estrogênio/metabolismo , Feminino , Indazóis/química , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.
RESUMO
A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II.
Assuntos
Antidepressivos/síntese química , Antidepressivos/farmacologia , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antidepressivos/química , Técnicas de Química Combinatória , Ciclopropanos/química , Humanos , Concentração Inibidora 50 , Milnaciprano , Estrutura Molecular , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of milnacipran analogs containing a heteroaromatic group were synthesized and studied as monoamine transporter inhibitors. Many compounds exhibited higher potency than milnacipran at NET and NET/SERT with no significant change in lipophilicity. For example, compound R-26f was about 10-fold more potent than milnacipran with IC(50) values of 8.7 and 26nM at NET and SERT, respectively.
Assuntos
Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Técnicas de Química Combinatória , Ciclopropanos/química , Humanos , Milnaciprano , Estrutura Molecular , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.
Assuntos
Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Química Farmacêutica/métodos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/síntese química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/farmacologia , Norepinefrina/química , Oxigênio/química , Inibidores da Captação Adrenérgica/química , Cloridrato de Atomoxetina , Citocromo P-450 CYP2D6/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Norepinefrina/metabolismo , Propilaminas/química , Propilaminas/farmacologia , Relação Estrutura-Atividade , Simportadores/químicaRESUMO
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Indanos/síntese química , Indanos/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Cloridrato de Atomoxetina , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Indanos/química , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Propilaminas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.
Assuntos
Antineoplásicos/administração & dosagem , Benzopiranos/química , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Administração Oral , Animais , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Ratos , Moduladores Seletivos de Receptor Estrogênico/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Cinamatos/administração & dosagem , Indazóis/administração & dosagem , Receptores de Estrogênio/administração & dosagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Xenoenxertos , Humanos , Camundongos , Estudos Prospectivos , Ratos , Resultado do TratamentoRESUMO
Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Proteólise/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Tamoxifeno/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cães , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Xenoenxertos , Humanos , Camundongos , Ratos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinéticaRESUMO
Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Tioidantoínas/uso terapêutico , Antagonistas de Androgênios/farmacocinética , Anilidas/farmacocinética , Anilidas/uso terapêutico , Animais , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacocinética , Benzamidas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Feniltioidantoína/análogos & derivados , Feniltioidantoína/sangue , Feniltioidantoína/farmacocinética , Feniltioidantoína/uso terapêutico , Ratos , Receptores Androgênicos/efeitos dos fármacos , Tioidantoínas/sangue , Tioidantoínas/síntese química , Tioidantoínas/farmacocinética , Compostos de Tosil/farmacocinética , Compostos de Tosil/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.