RESUMO
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
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
Assuntos
Indóis/farmacologia , Receptores de Grelina/agonistas , Sulfonamidas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Fluorescência , Indóis/síntese química , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1B de Serotonina/metabolismo , Receptores de Grelina/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
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
High-throughput screening resulted in the identification of a series of novel motilin receptor agonists with relatively low molecular weights. The series originated from an array of biphenyl derivatives designed to target 7-transmembrane (7-TM) receptors. Further investigation of the structure-activity relationship within the series resulted in the identification of compound (22) as a potent and selective agonist at the motilin receptor.
Assuntos
Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/química , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Química Farmacêutica/métodos , Técnicas de Química Combinatória , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Químicos , Estrutura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats.
Assuntos
Indóis/química , Receptores de Grelina/agonistas , Animais , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/fisiologia , Hormônio do Crescimento Humano/agonistas , Humanos , Indóis/farmacologia , Ratos , Receptores de Grelina/fisiologia , EstereoisomerismoRESUMO
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.
Assuntos
Antipsicóticos/síntese química , Benzazepinas/síntese química , Antagonistas de Dopamina/síntese química , Antagonistas dos Receptores de Dopamina D2 , Sulfonas/síntese química , Potenciais de Ação/efeitos dos fármacos , Administração Oral , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Disponibilidade Biológica , Células CHO , Catalepsia/induzido quimicamente , Cocaína/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Cricetinae , Dopamina/metabolismo , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacologia , Desenho de Fármacos , Humanos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Prolactina/sangue , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D3 , Relação Estrutura-Atividade , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/fisiologia , Sulfonas/farmacocinética , Sulfonas/farmacologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologiaRESUMO
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
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 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
Apelin peptides have recently been identified to be the endogenous ligands for the G protein-coupled receptor APJ. However, little is known about the physiological roles of this ligand-receptor pairing. In the present study we investigated the pharmacology of several apelin analogues at the human recombinant APJ receptor using radioligand binding and functional assays. This has led to the identification of key residues in the apelin peptide required for functional potency and binding affinity through structure-activity studies. In particular, we have identified that replacement of leucine in position 5, or arginine in position 2 and 4 of the C-terminal apelin peptide, apelin-13, resulted in significant changes in pharmacology. We also investigated the detailed localization of pre-proapelin and APJ receptor mRNA in a wide range of human, rat and mouse tissues using quantitative RT-PCR, and carried out a detailed immunohistochemical study of the distribution of the APJ receptor in rat brain and spinal cord. Interestingly, the APJ receptor was not only co-localized in white matter with GFAP in the spinal cord, but was also clearly localized on neurones in the brain, suggesting that this receptor and its peptide may be involved in a wide range of biological process yet to be determined.