RESUMO
The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.
Assuntos
Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Administração Oral , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Concentração Inibidora 50 , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Nitrogênio/química , Dor/tratamento farmacológico , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
Assuntos
Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade , Animais , Técnicas de Química Sintética , Cristalografia por Raios X , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/química , Ratos Wistar , Esquizofrenia/tratamento farmacológicoRESUMO
Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
Assuntos
Éteres/química , Antagonistas dos Receptores de Orexina , Piperidinas/química , Pirimidinas/química , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Éteres/síntese química , Éteres/farmacocinética , Meia-Vida , Humanos , Receptores de Orexina/metabolismo , Piperidinas/metabolismo , Ligação Proteica , Pirimidinas/metabolismo , Ratos , Sono/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethylâ (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.
Assuntos
Inibidores de Integrase de HIV/química , Oxidiazóis/química , Pró-Fármacos/química , Pirimidinonas/química , Pirrolidinonas/química , Acetais/química , Animais , Área Sob a Curva , Carbonatos/química , Cães , Avaliação Pré-Clínica de Medicamentos , Integrase de HIV/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , HIV-1/enzimologia , Meia-Vida , Hepatócitos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Curva ROC , Raltegravir Potássico , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Assuntos
Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacologia , Antagonistas dos Receptores de Orexina , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Receptores de Orexina/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
IMPORTANCE OF THE FIELD: The orexin neuropeptide system plays a central role in maintaining arousal and wakefulness. It has been demonstrated that small molecule antagonists to the orexin receptors promote sleep in preclinical species and in patients with insomnia. AREAS COVERED IN THIS REVIEW: This review provides a summary of published patent applications claiming novel orexin antagonists from 2006 to mid-2009, covering both selective and dual orexin receptor antagonists. WHAT THE READER WILL GAIN: Readers will gain an overview of orexin biology focusing on genetic and pharmacological validation of this target for treating sleep disorders. Additionally, this review discusses the importance of receptor subtype selectivity and the potential role of subtype selective and dual orexin antagonists in treating psychiatric illnesses beyond insomnia. This review identifies companies that are significant contributors to the patent literature claiming novel orexin receptor antagonists. TAKE HOME MESSAGE: The study of the orexin system has emerged as one of the key new fields of investigation in neuroscience. The demonstration of clinical proof-of-concept for the treatment of primary insomnia by Actelion in early 2007 has spurred significant interest in this field and competition has markedly increased since 2006.
Assuntos
Hipnóticos e Sedativos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Receptores de Orexina , Patentes como Assunto , Distúrbios do Início e da Manutenção do Sono/fisiopatologiaRESUMO
3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
Assuntos
Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Osteoporose/tratamento farmacológico , Receptores de Vitronectina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Concentração Inibidora 50 , Integrinas/metabolismo , Macaca mulatta , Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacocinética , Osteoporose/prevenção & controle , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements.
Assuntos
Aminoácidos/química , Ésteres/química , Receptores de Vitronectina/antagonistas & inibidores , Aminoácidos/síntese química , Aminoácidos/farmacocinética , Animais , Ácido Aspártico/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Ésteres/síntese química , Ésteres/farmacocinética , Humanos , Concentração Inibidora 50 , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Ligação Proteica , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.