RESUMO
The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.
Assuntos
Analgésicos Opioides/farmacologia , Morfinanos/farmacologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Analgésicos Opioides/química , Analgésicos Opioides/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Relação Dose-Resposta a Droga , Composição de Medicamentos , Humanos , Masculino , Morfinanos/química , Morfinanos/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/metabolismo , Fatores de TempoRESUMO
The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.
Assuntos
Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Pirazóis/síntese química , Pirimidinas/síntese química , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Solubilidade , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
Assuntos
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Animais , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Humanos , Camundongos , Microssomos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Pirazóis/química , Piridinas/químicaRESUMO
With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Compostos Azabicíclicos/química , Compostos Azabicíclicos/uso terapêutico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Ácidos Ftálicos/química , Ácidos Ftálicos/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Compostos Azabicíclicos/farmacocinética , Compostos Azabicíclicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Descoberta de Drogas , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Modelos Moleculares , Neoplasias/metabolismo , Neoplasias/patologia , Ácidos Ftálicos/farmacocinética , Ácidos Ftálicos/farmacologiaRESUMO
A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.
Assuntos
Trifosfato de Adenosina/metabolismo , Ligação Competitiva , Descoberta de Drogas , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Administração Oral , Animais , Benzoxazinas/química , Benzoxazinas/metabolismo , Benzoxazinas/farmacocinética , Benzoxazinas/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Cães , Feminino , Humanos , Masculino , Camundongos , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Especificidade por Substrato , Serina-Treonina Quinases TOR/químicaRESUMO
The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.