RESUMO
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
Assuntos
Descoberta de Drogas , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Receptores de Orexina , Piperidinas/síntese química , Piperidinas/química , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.
Assuntos
Indazóis/síntese química , Receptores de AMPA/fisiologia , Regulação Alostérica , Animais , Cálcio/metabolismo , Cristalografia por Raios X , Cães , Ensaios de Triagem em Larga Escala , Humanos , Técnicas In Vitro , Indazóis/farmacocinética , Indazóis/farmacologia , Ligantes , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Técnicas de Patch-Clamp , Multimerização Proteica , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/química , Proteínas Recombinantes/química , Solubilidade , Relação Estrutura-Atividade , Suínos , Porco MiniaturaRESUMO
A series of novel AMPA receptor positive modulators displaying CNS penetration have been discovered with sub-micromolar activity and good selectivity over the cardiac channel receptor, hERG. We describe here the synthesis of these compounds which are biaryl pyrrolidine and tetrahydrofuran sulfonamides and disclose their activities against the human GluA2 flip isoform homotetrameric receptor.
Assuntos
Furanos/farmacologia , Pirrolidinas/farmacologia , Receptores de AMPA/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Furanos/química , Humanos , Isoformas de Proteínas , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relação Estrutura-Atividade , SulfonamidasRESUMO
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Assuntos
Indenos/síntese química , Piridinas/síntese química , Receptores de AMPA/fisiologia , Sulfonamidas/síntese química , Administração Oral , Regulação Alostérica , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Barreira Hematoencefálica/metabolismo , Callithrix , Linhagem Celular , Cristalografia por Raios X , Cães , Humanos , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ligação Proteica , Estrutura Terciária de Proteína , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Assuntos
Quinolinas/farmacologia , Receptores 5-HT1 de Serotonina/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Ligantes , Quinolinas/administração & dosagem , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches for the treatment of depression.
Assuntos
Piperazinas/síntese química , Quinolinas/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Barreira Hematoencefálica/metabolismo , Córtex Cerebral/metabolismo , Humanos , Técnicas In Vitro , Piperazinas/farmacocinética , Piperazinas/farmacologia , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ensaio Radioligante , Ratos , Proteínas Recombinantes/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Assuntos
Receptores de Serotonina/metabolismo , Serotoninérgicos/metabolismo , Administração Oral , Disponibilidade Biológica , Ligantes , Serotoninérgicos/farmacocinéticaRESUMO
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
Assuntos
Benzoxazinas/síntese química , Benzoxazinas/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Callithrix , Linhagem Celular , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cricetinae , Cricetulus , Cobaias , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Piperazinas/farmacologia , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptor 5-HT1D de Serotonina/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacosRESUMO
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Assuntos
Amidas/química , Amidas/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bovinos , Biologia Computacional , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Enxofre/químicaRESUMO
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
Assuntos
Amidas/farmacologia , Compostos de Bifenilo/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Anilidas/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Humanos , Estrutura Molecular , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.
Assuntos
Benzoxazinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Benzoxazinas/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular , Estabilidade de Medicamentos , Humanos , Ensaio Radioligante , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-Atividade , Sinaptossomos/metabolismoRESUMO
At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.