RESUMO
Following the first CNS Anticancer Drug Discovery and Development Conference, the speakers from the first 4 sessions and organizers of the conference created this White Paper hoping to stimulate more and better CNS anticancer drug discovery and development. The first part of the White Paper reviews, comments, and, in some cases, expands on the 4 session areas critical to new drug development: pharmacological challenges, recent drug approaches, drug targets and discovery, and clinical paths. Following this concise review of the science and clinical aspects of new CNS anticancer drug discovery and development, we discuss, under the rubric "Accelerating Drug Discovery and Development for Brain Tumors," further reasons why the pharmaceutical industry and academia have failed to develop new anticancer drugs for CNS malignancies and what it will take to change the current status quo and develop the drugs so desperately needed by our patients with malignant CNS tumors. While this White Paper is not a formal roadmap to that end, it should be an educational guide to clinicians and scientists to help move a stagnant field forward.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Descoberta de Drogas , Glioma/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Intervalo Livre de Doença , Determinação de Ponto Final , Humanos , Resultado do TratamentoRESUMO
Anti-HER2 monoclonal antibodies (mAb) have been shown to reduce tumor size and increase survival in patients with breast cancer, but they are ineffective against brain metastases due to poor brain penetration. In previous studies, we identified a peptide, known as Angiopep-2 (An2), which crosses the blood-brain barrier (BBB) efficiently via receptor-mediated transcytosis, and, when conjugated, endows small molecules and peptides with this property. Extending this strategy to higher molecular weight biologics, we now demonstrate that a conjugate between An2 and an anti-HER2 mAb results in a new chemical entity, ANG4043, which retains in vitro binding affinity for the HER2 receptor and antiproliferative potency against HER2-positive BT-474 breast ductal carcinoma cells. Unlike the native mAb, ANG4043 binds LRP1 clusters and is taken up by LRP1-expressing cells. Measuring brain exposure after intracarotid delivery, we demonstrate that the new An2-mAb conjugate penetrates the BBB with a rate of brain entry (Kin) of 1.6 × 10(-3) mL/g/s. Finally, in mice with intracranially implanted BT-474 xenografts, systemically administered ANG4043 increases survival. Overall, this study demonstrates that the incorporation of An2 to the anti-HER2 mAb confers properties of increased uptake in brain endothelial cells as well as BBB permeability. These characteristics of ANG4043 result in higher exposure levels in BT-474 brain tumors and prolonged survival following systemic treatment. Moreover, the data further validate the An2-drug conjugation strategy as a way to create brain-penetrant biologics for neuro-oncology and other CNS indications.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacocinética , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Receptor ErbB-2/imunologia , Animais , Anticorpos Monoclonais/metabolismo , Antineoplásicos/síntese química , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Feminino , Células MCF-7 , Camundongos , Camundongos Nus , Peptídeos/síntese química , Peptídeos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor-related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.
Assuntos
Analgésicos/farmacologia , Nociceptividade/efeitos dos fármacos , Peptídeos/farmacologia , Succinimidas/farmacologia , Analgésicos/síntese química , Analgésicos/farmacocinética , Animais , Barreira Hematoencefálica/metabolismo , Neoplasias Ósseas/patologia , Permeabilidade Capilar , Linhagem Celular , Linhagem Celular Tumoral , Dor Crônica/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Formaldeído , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Peptídeos/síntese química , Peptídeos/farmacocinética , Ratos , Ratos Sprague-Dawley , Succinimidas/síntese química , Succinimidas/farmacocinéticaRESUMO
NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication.
Assuntos
Antieméticos/administração & dosagem , Antieméticos/metabolismo , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1/metabolismo , Compostos de Espiro/administração & dosagem , Compostos de Espiro/metabolismo , Administração Oral , Animais , Antieméticos/química , Células CHO , Células COS , Chlorocebus aethiops , Cricetinae , Cães , Feminino , Furões , Gerbillinae , Cobaias , Humanos , Macaca fascicularis , Camundongos , Ligação Proteica/fisiologia , Coelhos , Ratos , Compostos de Espiro/químicaRESUMO
A series of novel benzazepine derived dopamine D(1) antagonists have been discovered. These compounds are highly potent at D(1) and showed excellent selectivity over D(2) and D(4) receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D(1) and good selectivity over D(2)-like receptors.
Assuntos
Benzazepinas/química , Antagonistas de Dopamina/química , Receptores de Dopamina D1/antagonistas & inibidores , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/fisiologiaRESUMO
A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Assuntos
Benzazepinas/química , Benzazepinas/farmacologia , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores , Animais , Ratos , Receptores de Dopamina D1/fisiologiaRESUMO
The syntheses and SAR investigations of novel CB(1) receptor antagonists based on a 1,2-diaryl piperidine core have been described. Optimization of this core afforded a compound with robust in vivo potency by reducing food intake in a mouse DIO model.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Dieta/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Camundongos , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Piperidinas/administração & dosagem , Ligação Proteica/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel 1,3-benzodiazapine based D1 antagonists was designed according to the understanding of pharmacophore models derived from SCH 23390 (1b), a potent and selective D1 antagonist. The new design features an achiral cyclic-amidine that maintains desired basicity. Solid phase synthesis was developed for SAR development of the novel dopamine antagonists.
Assuntos
Benzodiazepinas/química , Antagonistas de Dopamina/química , Neurotransmissores/química , Receptores de Dopamina D1/antagonistas & inibidores , Benzazepinas/química , Benzazepinas/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Desenho de Fármacos , Humanos , Neurotransmissores/síntese química , Neurotransmissores/farmacologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Relação Estrutura-AtividadeRESUMO
The adenosine A(2A) receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A(2A) receptor (K(i) = 1.1 and 0.6 nM, respectively) and have >1000-fold selectivity over all other adenosine receptors, making these compounds the most selective A(2A) receptor antagonists reported to date. Both compounds attenuate hypolocomotion induced by the A(2A) receptor agonist CGS-21680 [2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine], suggesting that they inhibit A(2A) receptor activity in vivo. Their high degree of selectivity and robust in vivo activity make preladenant and SCH 412348 useful tools to investigate the role of the A(2A) receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3,4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A(2A) receptor antagonists and provide further evidence of the potential therapeutic benefits of A(2A) receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD).
Assuntos
Antagonistas do Receptor A2 de Adenosina , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Transtornos dos Movimentos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Pirimidinas/farmacologia , Triazóis/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Transtorno Depressivo/metabolismo , Humanos , Masculino , Camundongos , Transtornos dos Movimentos/metabolismo , Fármacos Neuroprotetores/química , Pirimidinas/química , Ratos , Receptor A2A de Adenosina/metabolismo , Triazóis/químicaRESUMO
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious gamma-lactam series of selective NK(1) antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.
Assuntos
Lactamas/química , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1/química , Administração Oral , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Modelos Químicos , Estrutura Molecular , Nitrogênio/química , Ligação Proteica , Relação Estrutura-Atividade , Substância P/química , Ureia/química , VômitoRESUMO
SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A(2A) receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A(2A) receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Química Farmacêutica/métodos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Pirimidinas/síntese química , Pirimidinas/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Desenho de Fármacos , Humanos , Modelos Químicos , Piperazinas/química , Quinolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A(2A) receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A(2A) receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 microM at physiological pH.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Química Farmacêutica/métodos , Doença de Parkinson/tratamento farmacológico , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinética , Adenosina/química , Administração Oral , Animais , Área Sob a Curva , Modelos Animais de Doenças , Desenho de Fármacos , Concentração de Íons de Hidrogênio , Modelos Químicos , Pirimidinas/química , Ratos , Solubilidade , Triazóis/química , Água/químicaRESUMO
A series of novel cyclobutane derivatives as potent and selective NK1 receptor antagonists is described. Several compounds in this series exhibited high in vitro binding affinity (Ki Assuntos
Ciclobutanos/farmacologia
, Antagonistas dos Receptores de Neurocinina-1
, Antagonistas da Serotonina/química
, Antagonistas da Serotonina/farmacologia
, Animais
, Sítios de Ligação
, Ciclobutanos/química
, Estereoisomerismo
, Relação Estrutura-Atividade
RESUMO
A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.
Assuntos
Ansiolíticos/química , Ansiolíticos/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Ansiolíticos/síntese química , Álcoois Benzílicos/química , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Flúor/química , Gerbillinae , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Relação Estrutura-Atividade , Ureia/síntese químicaRESUMO
To determine if A1 adenosine receptors mediate breast tumorigenesis, we evaluated A1 receptor expression in human tumor cell lines and human primary breast tumor tissues using both quantitative RT-PCR and Western blot analysis. A1 receptor mRNA expression is upregulated in all breast tumor cell lines examined (n=7) compared to normal mammary epithelial cells/cell lines (n=3) as determined by quantitative RT-PCR analysis. Western blot analysis indicates that protein expression of A1 adenosine receptor is higher in 15 (62.5%) of 24 human primary breast tumor tissues than in matched normal breast tissue. To explore its cellular function, the A1 adenosine receptor was depleted by small interfering RNA (siRNA) in MDA-MB-468 human breast tumor cells. Depletion of A1 receptors in MDA-MB-468 breast tumor cells attenuated both cell growth and cell proliferation as measured by cell number counts and [(14)C]-thymidine incorporation, respectively. Cell cycle analysis indicated that depletion of A1 receptors by siRNA impairs G(1) checkpoint, leading to marked accumulation of cells in G(2)/M phase, in agreement with the inhibitory effect on cell proliferation. Further supporting this finding, synchronization studies of Hela cells in various cell cycle phases suggest that A1 receptor expression is suppressed in G(2)/M cells and depletion of A1 receptor expression by siRNA produced differential expression of several key cell cycle regulators, i.e., accumulation of the cyclin-dependent kinase inhibitor p27 with concomitant reduction of CDK4 and cyclin E proteins. In addition to the impact on cell cycle progression, depletion of A1 receptors by siRNA results in substantial cell death and apoptosis as determined by FACS analysis and annexin V staining method. Together these findings suggest that the A1 adenosine receptor may contribute to tumor cell growth and survival in breast tumor cells.
Assuntos
Apoptose , Neoplasias da Mama/patologia , Carcinoma/patologia , Proliferação de Células , Interferência de RNA , Receptor A1 de Adenosina/metabolismo , Mama/citologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Mensageiro/metabolismoRESUMO
A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Ureia/análogos & derivados , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Gerbillinae , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/farmacologia , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
Benzazepines 1 and 2 (SCH 23390 and SCH 39166, respectively) are two classical benzazepine D1/D5 antagonists, with Ki values 1.4 and 1.2 nM, respectively. Compound 2 has been in human clinical trials for a variety of diseases, including schizophrenia, cocaine addition, and obesity. Both 1 and 2 displayed low plasma levels and poor oral bioavailability, due to rapid first-pass metabolism of the phenol moieties. Several heterocyclic systems containing an N-H hydrogen bond donor were synthesized and evaluated as phenol isosteres. The preference orientation of the hydrogen bond was established by comparison of analogues containing different NH vectors. Replacement of the phenol group of 2 with an indole ring generated the first potent D1/D5 antagonist 11b. Further optimization led to the synthesis of very potent benzimidazolones 19, 20 and benzothiazolone analogues 28, 29. These compounds have excellent selectivity over D2-D4 receptors, alpha2a receptor, and the 5-HT transporter. Compared to 2, these heterocyclic phenol isosteres showed much better pharmacokinetic profiles as demonstrated by rat plasma levels. In sharp contrast, similar phenolic replacements in 1 decreased the binding affinity dramatically, presumably due to a conformational change of the pendant phenyl group. However, one indazole compound 33 was identified as a potent D1/D5 ligand in this series.
Assuntos
Benzazepinas/síntese química , Antagonistas de Dopamina/síntese química , Fenóis/síntese química , Receptores de Dopamina D1/antagonistas & inibidores , Animais , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Linhagem Celular , Cricetinae , Cricetulus , AMP Cíclico/biossíntese , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacologia , Desenho de Fármacos , Masculino , Modelos Moleculares , Fenóis/farmacocinética , Fenóis/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D5 , Relação Estrutura-AtividadeRESUMO
The functional specificity of dopamine receptor subtypes remains incompletely understood, in part due to the absence of highly selective agonists and antagonists. Phenotypic analysis of dopamine receptor knockout mice has been instrumental in identifying the role of dopamine receptor subtypes in mediating dopamine's effects on motor function, cognition, reward, and emotional behaviors. In this article, we provide an update of recent studies in dopamine receptor knockout mice and discuss the limitations and future promise of this approach.
Assuntos
Fenótipo , Receptores Dopaminérgicos/deficiência , Receptores Dopaminérgicos/genética , Animais , Emoções/fisiologia , Humanos , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Subunidades Proteicas/classificação , Subunidades Proteicas/deficiência , Subunidades Proteicas/genética , Receptores Dopaminérgicos/classificaçãoRESUMO
Low molecular weight amide derivatives were synthesized and evaluated as M(2) receptor antagonists for the treatment of Alzheimer's disease. Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M(2) receptor antagonists with structural features different from our clinical candidate 1.