RESUMO
A series of CCK2R-selective anthranilic amides is shown to derive CCK1R affinity via selective substitution of the amide side chain. Thus, extending the length of the original benzamide side chain by a single methylene unit imparts CCK1R affinity to the series, and further fine tuning of the affinity results in CCK1R selectivity of greater than 100-fold.
Assuntos
Isoxazóis/química , Receptor de Colecistocinina A/antagonistas & inibidores , Receptor de Colecistocinina B/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Benzamidas/farmacologia , Clonagem Molecular , Avaliação Pré-Clínica de Medicamentos , Genótipo , Aprendizagem em Labirinto , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina A/genética , Receptor de Colecistocinina A/metabolismo , Receptor de Colecistocinina B/genética , Receptor de Colecistocinina B/metabolismo , Relação Estrutura-AtividadeRESUMO
In the previous article we demonstrated how certain CCK2R-selective anthranilic amides could be structurally modified to afford high-affinity, selective CCK1R activity. We now describe our efforts at modulating and optimizing the CCK1R and CCK2R affinities aimed at producing compounds with good pharmacokinetics properties and in vivo efficacy in rat models of gastric acid and pancreatic amylase secretion.
Assuntos
Isoxazóis/química , Receptor de Colecistocinina A/antagonistas & inibidores , Receptor de Colecistocinina B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Substituição de Aminoácidos , Animais , Modelos Moleculares , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
A series of indeno[1,2-c]pyrazoles were discovered to be the first known inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase. The synthesis, structure-activity relationship profile, and in-vitro pharmacological characterization of this inaugural series of HRI kinase inhibitors are detailed.
Assuntos
Descoberta de Drogas , Heme/metabolismo , Indenos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , eIF-2 Quinase/antagonistas & inibidores , Indenos/síntese química , Indenos/química , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade , eIF-2 Quinase/metabolismoRESUMO
A novel series of cholecystokinin-2 receptor (CCK-2R) antagonists has been identified, as exemplified by anthranilic sulfonamide 1 (pK(i)=7.6). Pharmacokinetic and stability studies indicated that this series of compounds suffered from metabolic degradation, and that both the benzothiadiazole and piperidine rings were rapidly oxidized by liver enzymes. A combination of synthesis, computational methods, (1)H NMR conformational studies, and X-ray crystallographic analyses were applied to elucidate key pharmacophore elements, and to discover analogs with improved pharmacokinetic profiles, and high receptor binding affinity and selectivity.
Assuntos
Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Benzotiazóis/síntese química , Benzotiazóis/química , Benzotiazóis/farmacologia , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Receptor de Colecistocinina A/metabolismo , Receptor de Colecistocinina B/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
A novel strategy for the synthesis of cholecystokinin-2 receptor ligands was developed. The route employs a solution-phase synthesis of a series of anthranilic sulfonamides followed by a resin capture purification strategy to produce multi-milligram quantities of compounds for bioassay. The synthesis was used to produce >100 compounds containing various functional groups, highlighting the general applicability of this strategy and to address specific metabolism issues in our CCK-2 program.
Assuntos
Colecistocinina/metabolismo , Técnicas de Química Combinatória , Receptor de Colecistocinina B/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Animais , Desenho de Fármacos , Humanos , Ligantes , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , ortoaminobenzoatos/químicaRESUMO
A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.
Assuntos
Morfolinas/síntese química , Quinoxalinas/síntese química , Receptor de Colecistocinina B/antagonistas & inibidores , Sulfonamidas/síntese química , ortoaminobenzoatos/síntese química , Animais , Ligação Competitiva , Disponibilidade Biológica , Cães , Estabilidade de Medicamentos , Vesícula Biliar/efeitos dos fármacos , Vesícula Biliar/fisiologia , Ácido Gástrico/metabolismo , Cobaias , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Morfolinas/química , Morfolinas/farmacologia , Contração Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina A/antagonistas & inibidores , Estereoisomerismo , Estômago/efeitos dos fármacos , Estômago/fisiologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologiaRESUMO
Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX(1)R and OX(2)R). In addition to other biological functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX(2)R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is compound 9, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea, which is bound by the OX(2)R with a pK(i) of 8.3, has a pK(b) of 7.9, and is 600-fold selective for the OX(2)R over the OX(1)R.