RESUMO
INTRODUCTION: Histaminergic H3 receptors may play a role in modulating cholinergic and monoaminergic neurotransmission. This Phase II study evaluated the efficacy and safety of GSK239512, a highly potent, brain penetrant H3 receptor antagonist as monotherapy treatment for subjects with mild-to-moderate probable Alzheimer's disease (AD). METHODS: In this 16-week, double-blind, randomized, parallel group study, 196 currently untreated subjects with mild-tomoderate AD (Mini Mental State Examination [MMSE] 16-24) received GSK239512 (n=97); or placebo (n=99) administered orally each morning. After a two-week placebo run-in period GSK239512 was up-titrated over 4 weeks in a flexible manner (10-20-40-80 microgram [µg]) followed by a 12-week Maintenance Phase. Co-primary efficacy endpoints were change from baseline in Episodic Memory and Executive Function/Working Memory composite scores from the CogState neuropsychological test battery (NTB) at Week 16. RESULTS: Compared to placebo, GSK239512 improved Episodic Memory at Week 16 (Effect Size [ES] =0.35; p=0.0495). No statistically significant differences were observed on other cognitive domains or on clinical measures including the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADASCog). GSK239512 treatment was associated with mild to moderate adverse events with headache, dizziness and events related to sleep disturbances being the most common and more pronounced in the early titration period when subjects were first being exposed to GSK239512 at the lower 10µg and 20µg doses. There were no clinically relevant changes in other safety parameters. CONCLUSION: GSK239512, at doses up to 80µg/day, improved Episodic Memory in patients with mildto- moderate AD. However, no improvements were observed on Executive Function/Working Memory or other domains of cognition. No changes were observed on any of the clinical measures included as secondary endpoints (including ADAS-Cog) indicating that GSK239512 failed to show benefit in this population. GSK239512 had an acceptable safety and tolerability profile. These findings suggest that H3 antagonists may, at most, have modest and selective effects on cognitive function in patients with mild-to-moderate AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzazepinas/uso terapêutico , Nootrópicos/uso terapêutico , Idoso , Benzazepinas/efeitos adversos , Método Duplo-Cego , Função Executiva/efeitos dos fármacos , Feminino , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Masculino , Adesão à Medicação , Memória Episódica , Memória de Curto Prazo/efeitos dos fármacos , Testes Neuropsicológicos , Nootrópicos/efeitos adversos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
Assuntos
Benzazepinas/química , Antagonistas dos Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Animais , Benzazepinas/farmacocinética , Cães , Meia-Vida , Haplorrinos , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Niacinamida/análogos & derivados , Niacinamida/química , Niacinamida/farmacocinética , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Assuntos
Benzazepinas/química , Antagonistas dos Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Animais , Benzazepinas/síntese química , Benzazepinas/farmacocinética , Citocromo P-450 CYP2D6/química , Citocromo P-450 CYP2D6/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Ligação Proteica , Ratos , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-AtividadeRESUMO
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.
Assuntos
Benzazepinas/farmacologia , Encéfalo/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Niacinamida/análogos & derivados , Nootrópicos/farmacologia , Receptores Histamínicos H3/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Benzazepinas/metabolismo , Benzazepinas/farmacocinética , Ligação Competitiva , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Cães , Agonistas dos Receptores Histamínicos/metabolismo , Agonistas dos Receptores Histamínicos/farmacocinética , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/metabolismo , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , Neurotransmissores/metabolismo , Niacinamida/metabolismo , Niacinamida/farmacocinética , Niacinamida/farmacologia , Nootrópicos/metabolismo , Nootrópicos/farmacocinética , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores Histamínicos H3/análise , Sus scrofaRESUMO
Stroke is the third leading cause of death and the leading cause of disability in developed countries, yet remains a poorly treated condition. Treatments for stroke can be aimed at acutely improving blood flow or protecting brain tissue against ischaemia, enhancing stroke recovery or reducing the risk of stroke recurrence. This paper reviews each of these approaches, particularly focusing on mechanisms for which there are agents in clinical trials. There are a number of appealing neuroprotective agents in Phase II and III clinical trials. However, the majority of acute treatments are likely to suffer from a narrow therapeutic time window and hence limited patient access. Combinations of acute approaches are likely to offer the greatest benefit, but present challenges in development. Promotion of recovery following stroke offers enormous potential for successful therapeutic intervention. Excitingly, new developments in preclinical research have identified possible ways in which this may be achieved.