RESUMO
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
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
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
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
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
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.
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
An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.
Assuntos
Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/síntese química , Animais , Humanos , Ligantes , Microssomos Hepáticos , Ratos , Antagonistas da Serotonina/farmacologia , 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
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
BACKGROUND: SB-236057 is a potent skeletal teratogen in rodents and rabbits, producing axial and posterior somite malformations in cultured rat embryos. The compound shares some structural similarity to cyclopamine. METHODS: M13 phage display was used to identify amino acid motifs with binding affinity to SB-236057. A 10 microM SB-236057 solution was administered to cultured day 9 postcoitus rat embryos and real-time PCR was conducted at 6 hr posttreatment to evaluate early transcriptional response of axial development genes. Whole-mount in situ hybridization of selected transcripts was conducted on embryos at 48 hr post-compound administration. The rat-enhancer of split protein 1 (r-esp1) expression-functional characterization was done by transcriptional expression and morpholino antisense approaches. RESULTS: We identified several amino acid motifs that had high binding affinity to SB-236057-biotin conjugates, one with 100% sequence homology to a region of r-esp1, one of the Groucho homologs transcribed by the enhancer of split complex (En[spl]C). SB-236057 repressed expression of r-esp1 and members of the Notch-En[spl]C pathway. Goosecoid and HNF3-beta, both suspected to associate with Groucho proteins, were also responsive, although expression of another putative binding protein, engrailed-1 (en-1), and other en-1 pathway members was not affected. R-esp1 mRNA was localized along the axis and antisense inhibition produced similar somite malformations as SB-236057 did. At 48 hr post-SB-236057 or post-r-esp1 antisense administration, affected embryos demonstrated unchanged sonic hedgehog (shh) expression, however HNF3-beta expression was either absent, altered, or reduced. CONCLUSIONS: We present experimental evidence that the mechanism of SB-236057 teratogenicity includes transcriptional alterations to the Notch1-En[spl] pathway. In addition, alterations in HNF3-beta expression were similar to those induced by cyclopamine. The relationships between r-esp1 with Notch1 and shh signaling pathways and potential mechanisms of SB-236057 teratogenicity are also discussed.
Assuntos
Padronização Corporal/efeitos dos fármacos , Indóis/toxicidade , Piridinas/toxicidade , Antagonistas da Serotonina/toxicidade , Teratogênicos/toxicidade , Animais , Bacteriófago M13/genética , Sequência de Bases , Primers do DNA , Proteínas de Ligação a DNA/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fator 3-beta Nuclear de Hepatócito , Hibridização In Situ , Microscopia Confocal , Proteínas Nucleares/genética , Gravidez , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genéticaRESUMO
Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor.
Assuntos
Compostos de Aminobifenil/farmacologia , Receptores de Droga/antagonistas & inibidores , Animais , Sítios de Ligação , Cálcio/análise , Cálcio/metabolismo , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Linhagem Celular , Eletrofisiologia , Fluorescência , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Aumento da Imagem , Técnicas de Patch-Clamp , Ratos , Receptores de Droga/química , Relação Estrutura-Atividade , Canais de Cátion TRPVRESUMO
Starting from a series of 7-linked tetrahydroisoquinoline derivatives, as exemplified by SB-270664, a new series of 8,8-dimethylnaphthyridine compounds has been identified. SAR studies around these attractive leads have provided compounds such as 12 which display excellent anticonvulsant activity and an encouraging pharmacokinetic profile in vivo.