RESUMO
GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model.
Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas G/agonistas , Tetrazóis/farmacologia , Tiofenos/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química , Tiofenos/químicaRESUMO
The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Pirróis/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo N/metabolismo , Neuralgia/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Descoberta de Drogas , Células HEK293 , Humanos , Masculino , Neuralgia/metabolismo , Técnicas de Patch-Clamp , Piranos/química , Piranos/farmacologia , Piranos/uso terapêutico , Pirazóis/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The discovery of a novel series of cyclopenta[b]furans as CCR2 inhibitors is discussed. This series has excellent CCR2 potency and PK characteristics, and good cardiovascular safety.
Assuntos
Furanos/química , Furanos/farmacologia , Receptores CCR2/antagonistas & inibidores , Linhagem Celular , Quimiocina CCL2/imunologia , Humanos , Receptores CCR2/imunologiaRESUMO
A novel series of substituted tetrahydropyrrolo[3,4-c]pyrazoles were investigated as blockers of the N-type calcium channel (Cav2.2 channels), a chronic pain target.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/metabolismo , Dor Crônica/tratamento farmacológico , Humanos , Microssomos Hepáticos/metabolismo , Pirazóis/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
A novel series of substituted 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles were investigated as N-type calcium channel blockers (Cav2.2 channels), a chronic pain target. One compound was active in vivo in the rat CFA pain model.
Assuntos
Analgésicos/química , Analgésicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Analgésicos/metabolismo , Analgésicos/farmacocinética , Animais , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacocinética , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Pirazóis/metabolismo , Pirazóis/farmacocinética , RatosRESUMO
Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.
Assuntos
Analgésicos/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/metabolismo , Dor Crônica/tratamento farmacológico , Neuralgia/tratamento farmacológico , Piperidinas/síntese química , Pirazóis/síntese química , Analgésicos/uso terapêutico , Animais , Bloqueadores dos Canais de Cálcio/uso terapêutico , Linhagem Celular , Dor Crônica/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Neuralgia/metabolismo , Técnicas de Patch-Clamp , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Relação Estrutura-Atividade , ômega-Conotoxinas/uso terapêuticoRESUMO
GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due to increased insulin and GLP-1 secretion, with the added benefit of promoting weight loss. In our search for potent GPR40 full agonists, we discovered a superagonist which displayed excellent in vitro potency and superior efficacy in the Gαs-mediated signaling pathway. Most synthetic GPR40 agonists have a carboxylic acid headgroup, which may cause idiosyncratic toxicities, including drug-induced-liver-injury (DILI). With a methyl group and a fluorine atom substituted at the α-C of the carboxylic acid group, 19 is not only highly efficacious in lowering glucose and body weight in rodent models but also has a low DILI risk due to its stable acylglucuronide metabolite.
RESUMO
A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Pulmão/efeitos dos fármacos , Receptores de Interleucina-8B/antagonistas & inibidores , Sulfonamidas/química , Ácidos Sulfônicos/química , Compostos de Sulfonilureia/química , Administração Oral , Animais , Animais Recém-Nascidos , Disponibilidade Biológica , Lavagem Broncoalveolar , Ácidos Carboxílicos/farmacocinética , Quimiotaxia/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Hiperóxia , Pulmão/metabolismo , Lesão Pulmonar , Estrutura Molecular , Neutrófilos/metabolismo , Coelhos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of novel 5-aminomethyl-1H-benzimidazole based inhibitors of Itk were prepared. Structure-activity relationships, selectivity and cell activity are reported for this series. Compound 2, a potent and selective antagonist of Itk, inhibited anti-CD3 antibody induced IL-2 production in vivo in mice.
Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/química , Benzimidazóis/síntese química , Química Farmacêutica/métodos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Administração Oral , Animais , Benzimidazóis/farmacologia , Complexo CD3/biossíntese , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Modelos Químicos , Relação Estrutura-Atividade , Linfócitos T/citologiaRESUMO
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Assuntos
Amidas/química , Benzimidazóis/química , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Microssomos Hepáticos/metabolismo , Proteínas Tirosina Quinases/química , Animais , Benzimidazóis/síntese química , Ácidos Carboxílicos/síntese química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
Assuntos
Benzimidazóis/química , Química Farmacêutica/métodos , Inibidores de Proteínas Quinases/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/química , Benzimidazóis/síntese química , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Químicos , Ligação Proteica , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Pyrrolidin-2-one (gamma-lactam) derivatives have shown a wide range of activities as ligands to diverse receptors, e.g., integrin, CCR5, and CCK. Therefore, we have prepared a large library of these derivatives for high-throughput screening against various protein targets, after developing a synthesis of pyrrolidin-2-ones on solid phase. Exploration of the ring formation was key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-protected amino acids and subsequent deprotection of the Fmoc group were accomplished readily. The resulting resin-bound primary amines were treated with beta-monomethyl itaconate under gentle heat in a mixture of methanol and toluene to yield the desired intermediates. Finally, saponification, amide formation, and cleavage from the resin led to the production of a library of 12,000 pyrrolidin-2-one derivatives. These products were isolated as diastereomeric mixtures of high purity and were obtained in good yields.
RESUMO
The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.