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
Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.
Assuntos
Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Animais , Sítios de Ligação , Células CHO , Química Farmacêutica , Cricetinae , Cricetulus , Desenho de Fármacos , Descoberta de Drogas , Modelos Químicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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
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
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Assuntos
Antidepressivos Tricíclicos/síntese química , Encéfalo/efeitos dos fármacos , Química Farmacêutica/métodos , Receptores de Serotonina/química , Antagonistas da Serotonina/síntese química , Animais , Antidepressivos Tricíclicos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/química , Humanos , Ligação de Hidrogênio , Microssomos/efeitos dos fármacos , Modelos Químicos , Conformação Molecular , Isoformas de Proteínas , Ratos , Antagonistas da Serotonina/farmacologiaRESUMO
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.
Assuntos
Doença de Alzheimer/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Técnicas de Química Combinatória , Etilaminas/síntese química , Etilaminas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Cristalografia por Raios X , Etilaminas/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
Assuntos
Doença de Alzheimer/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Técnicas de Química Combinatória , Etilaminas/síntese química , Etilaminas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Animais , Asparagina/química , Cristalografia por Raios X , Modelos Animais de Doenças , Etilaminas/química , Flúor/química , Camundongos , Estrutura Molecular , Nanotecnologia , Relação Estrutura-AtividadeRESUMO
This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Técnicas de Química Combinatória , Etilaminas/síntese química , Etilaminas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Cristalografia por Raios X , Etilaminas/química , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
Assuntos
Carbono/química , Piridinas/química , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Gastrinas/química , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Piridinas/síntese química , Piridinas/farmacologia , Coelhos , Ratos , Receptores dos Hormônios Gastrointestinais/química , Receptores de Neuropeptídeos/químicaRESUMO
On June 15, 2006, the Society for Medicines Research held a one-day meeting in Harlow, United Kingdom, entitled Translational Sciences-Turning Drug-like Molecules into Medicines. The meeting brought together speakers from Europe representing the pharmaceutical industry and provided an overview on some of the latest approaches in a range of areas such as predictive toxicology, translational biology, in vitro-in vivo extrapolation, pharmacokinetic/pharmacodynamic modeling, and the use of biomarkers and surrogate endpoints.
Assuntos
Desenho de Fármacos , Tratamento Farmacológico , Farmacocinética , Toxicologia , Animais , Humanos , Modelos AnimaisRESUMO
dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.
Assuntos
Encéfalo/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Antagonistas de Dopamina/uso terapêutico , Antagonistas dos Receptores de Dopamina D2 , Recompensa , Tetra-Hidroisoquinolinas , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/fisiopatologia , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Condicionamento Operante/efeitos dos fármacos , Antagonistas de Dopamina/efeitos adversos , Relação Dose-Resposta a Droga , Estimulação Elétrica , Eletrodos Implantados , Haloperidol/efeitos adversos , Haloperidol/uso terapêutico , Masculino , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Reforço Psicológico , Prevenção Secundária , Autoadministração , Comportamento Espacial/efeitos dos fármacosRESUMO
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
N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.
Assuntos
Descoberta de Drogas , Fármacos Gastrointestinais/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Antro Pilórico/efeitos dos fármacos , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Animais , Cães , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Contração Muscular/efeitos dos fármacos , Piperazinas/química , Piperidinas/química , Antro Pilórico/fisiologia , Coelhos , RatosRESUMO
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
A concise and convergent eight-step synthesis of the antifungal metabolite monocerin 1 is reported. The key step involves an allylsilane metathesis/aldehyde condensation sequence to establish the core 2,3,5-trisubstituted tetrahydrofuran. End-game approaches based around intramolecular Heck chemistry revealed an interesting example of formal 6-endo cyclisation, the origin of which was probed using model substrates. The synthesis was ultimately completed by a strategy involving stepwise oxidative cleavage of the C3-ethenyl substituent.
Assuntos
Lactonas/síntese química , Lactonas/química , Estrutura Molecular , EstereoisomerismoRESUMO
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
Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Animais , Capsaicina/farmacologia , Linhagem Celular , Desenho de Fármacos , Cobaias , Humanos , Estrutura Molecular , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo , Ureia/administração & dosagem , Ureia/síntese química , 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.