RESUMO
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
A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.
Assuntos
Imidazolinas/farmacologia , Antagonistas Purinérgicos/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Haplorrinos , Imidazolinas/administração & dosagem , Imidazolinas/química , Imidazolinas/farmacocinética , Antagonistas Purinérgicos/administração & dosagem , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/farmacocinética , RatosRESUMO
A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
Assuntos
Amidas/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Ácido Pirrolidonocarboxílico/química , Receptores Purinérgicos P2X7/efeitos dos fármacos , Amidas/química , Descoberta de Drogas , Modelos Moleculares , Antagonistas do Receptor Purinérgico P2/química , Relação Estrutura-AtividadeRESUMO
As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
Assuntos
Química Farmacêutica/métodos , Grelina/química , Receptores de Grelina/antagonistas & inibidores , Sulfonas/química , Administração Oral , Animais , Disponibilidade Biológica , Desenho de Fármacos , Hormônio do Crescimento/química , Masculino , Modelos Químicos , Processamento de Proteína Pós-Traducional , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/química , Relação Estrutura-AtividadeRESUMO
Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Furanos/síntese química , Furanos/farmacologia , Indanos/síntese química , Indanos/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Animais , Furanos/química , Imidazóis/química , Imidazóis/farmacologia , Indanos/química , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Ratos , Acidente Vascular Cerebral/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
