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
6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.
Assuntos
Benzotiazóis/síntese química , Química Farmacêutica/métodos , Niacinamida/análogos & derivados , Niacinamida/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/química , Administração Oral , Animais , Benzotiazóis/farmacologia , Capsaicina/química , Linhagem Celular , Desenho de Fármacos , Cobaias , Humanos , Inflamação , Concentração Inibidora 50 , Modelos Químicos , Niacinamida/química , Niacinamida/farmacologia , RatosRESUMO
Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), which has now entered clinical trials. Using a Ca(2+)-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pK(i) = 7.6) with activity at rat (pK(i) = 7.5) and guinea pig (pK(i) = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC(50) = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) = 6 nM)-mediated activation of human TRPV1 (at -70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.
Assuntos
Ácidos/farmacologia , Capsaicina/farmacologia , Temperatura Alta , Pirrolidinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Ligação Competitiva/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Eletrofisiologia , Cobaias , Humanos , Concentração de Íons de Hidrogênio , Potenciais da Membrana/efeitos dos fármacos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-Clamp , Pirrolidinas/química , Ratos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/fisiologia , Transfecção , Ureia/química , Ureia/farmacologiaRESUMO
Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.
Assuntos
Benzamidas/química , Benzamidas/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Benzamidas/síntese química , Capsaicina/farmacologia , Cobaias , Humanos , Isoquinolinas/síntese química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estrutura Molecular , Quinolinas/síntese química , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
Bisaryl cyclic ureas have been identified as high affinity 5-HT2C receptor antagonists with selectivity over 5-HT2A and 5-HT2B. Compounds such as 8 and 22 have shown oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function in rodents.
Assuntos
Imidazolidinas/administração & dosagem , Imidazolidinas/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina , Administração Oral , Animais , Linhagem Celular , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Estrutura Molecular , Ratos , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
Assuntos
Encéfalo/metabolismo , Piperazinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Cães , Conformação Molecular , Permeabilidade , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.