RESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Ghrelina/química , Receptores de Ghrelina/antagonistas & inhibidores , Sulfonas/química , Administración Oral , Animales , Disponibilidad Biológica , Diseño de Fármacos , Hormona del Crecimiento/química , Masculino , Modelos Químicos , Procesamiento Proteico-Postraduccional , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/química , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/química , Animales , Sitios de Unión , Membrana Celular/metabolismo , Química Farmacéutica/métodos , Técnicas Químicas Combinatorias , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Modelos Químicos , Estructura Molecular , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzotiazoles/síntesis química , Química Farmacéutica/métodos , Niacinamida/análogos & derivados , Niacinamida/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/química , Administración Oral , Animales , Benzotiazoles/farmacología , Capsaicina/química , Línea Celular , Diseño de Fármacos , Cobayas , Humanos , Inflamación , Concentración 50 Inhibidora , Modelos Químicos , Niacinamida/química , Niacinamida/farmacología , RatasRESUMEN
A series of small molecule orally bioavailable ghrelin receptor agonists have been identified through systematic optimisation of a high throughput screening hit.
Asunto(s)
Indoles/farmacología , Receptores de Ghrelina/agonistas , Sulfonamidas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Fluorescencia , Indoles/síntesis química , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1B/metabolismo , Receptores de Ghrelina/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
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.
Asunto(s)
Indoles/química , Receptores de Ghrelina/agonistas , Animales , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/fisiología , Hormona de Crecimiento Humana/agonistas , Humanos , Indoles/farmacología , Ratas , Receptores de Ghrelina/fisiología , EstereoisomerismoRESUMEN
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.
Asunto(s)
Ácidos/farmacología , Capsaicina/farmacología , Calor , Pirrolidinas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Unión Competitiva/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Línea Celular , Células Cultivadas , Relación Dosis-Respuesta a Droga , Electrofisiología , Cobayas , Humanos , Concentración de Iones de Hidrógeno , Potenciales de la Membrana/efectos de los fármacos , Estructura Molecular , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Técnicas de Placa-Clamp , Pirrolidinas/química , Ratas , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/fisiología , Transfección , Urea/química , Urea/farmacologíaRESUMEN
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.
Asunto(s)
Amidas/química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bovinos , Biología Computacional , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Azufre/químicaRESUMEN
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.
Asunto(s)
Amidas/farmacología , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Anilidas/química , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Humanos , Estructura Molecular , Receptores de Somatostatina/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Benzamidas/síntesis química , Capsaicina/farmacología , Cobayas , Humanos , Isoquinolinas/síntesis química , Hígado/efectos de los fármacos , Hígado/metabolismo , Estructura Molecular , Quinolinas/síntesis química , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
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.
Asunto(s)
Encéfalo/metabolismo , Piperazinas/síntesis química , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Barrera Hematoencefálica , Perros , Conformación Molecular , Permeabilidad , Piperazinas/farmacocinética , Piperazinas/farmacología , Ratas , Antagonistas de la Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antipsicóticos/síntesis química , Benzazepinas/síntesis química , Antagonistas de Dopamina/síntesis química , Antagonistas de los Receptores de Dopamina D2 , Sulfonas/síntesis química , Potenciales de Acción/efectos de los fármacos , Administración Oral , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Disponibilidad Biológica , Células CHO , Catalepsia/inducido químicamente , Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Cricetinae , Dopamina/metabolismo , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacología , Diseño de Fármacos , Humanos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Prolactina/sangre , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D3 , Relación Estructura-Actividad , Sustancia Negra/citología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiología , Sulfonas/farmacocinética , Sulfonas/farmacología , Área Tegmental Ventral/citología , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiologíaRESUMEN
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.