RESUMO
Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.
Assuntos
6-Aminonicotinamida/análogos & derivados , 6-Aminonicotinamida/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Citocromo P-450 CYP3A/metabolismo , Agonismo Inverso de Drogas , Receptores de Grelina/agonistas , 6-Aminonicotinamida/metabolismo , Fármacos Antiobesidade/metabolismo , Descoberta de Drogas , Humanos , Microssomos Hepáticos/metabolismo , Obesidade/tratamento farmacológico , Receptores de Grelina/metabolismoRESUMO
A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.
Assuntos
Fármacos Antiobesidade/química , Receptores de Grelina/agonistas , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacocinética , Modelos Animais de Doenças , Agonismo Inverso de Drogas , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Niacinamida/administração & dosagem , Niacinamida/química , Niacinamida/farmacocinética , Obesidade/tratamento farmacológico , Obesidade/patologia , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/metabolismo , Relação Estrutura-AtividadeRESUMO
New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.
Assuntos
Niacinamida/análogos & derivados , Receptores de Grelina/agonistas , Receptores de Grelina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Regulação do Apetite/efeitos dos fármacos , Desenho de Fármacos , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Niacinamida/química , Niacinamida/farmacologia , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of truncated analogs of α-galactosylceramide with altered ceramide moiety was prepared, and evaluated for Th2-biased response in the context of IL-4/IFN-γ ratio. Phytosphingosine-modified analogs including cyclic, aromatic and ethereal compounds as well as the C-glycoside analog of OCH (2) with their cytokine inducing profile are disclosed.
Assuntos
Galactosilceramidas/química , Galactosilceramidas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-4/metabolismo , Animais , Antígenos CD1d/química , Antígenos CD1d/metabolismo , Sítios de Ligação , Simulação por Computador , Galactosilceramidas/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Células Th2/efeitos dos fármacosRESUMO
Analogs of immunomodulatory glycolipid OCH (2) were prepared and minimum structure requirement to exhibit equivalent profiles was disclosed. Analogs bearing non-linear hydrocarbon chain in the phytosphingosine moiety (18, 19) were shown for the first time to possess comparable cytokine inducing profile to 2. Molecular modeling of 2/hCD1d complex based on the crystal structure of alpha-GalCer (1)/hCD1d complex is also described.
Assuntos
Citocinas/metabolismo , Glicolipídeos/metabolismo , Fatores Imunológicos/metabolismo , Esfingosina/análogos & derivados , Células Th2/metabolismo , Animais , Humanos , Estrutura Molecular , Esfingosina/químicaRESUMO
[reaction: see text] A practical and efficient total synthesis of (2S,3S,4R)-1-O-(alpha-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonanetriol, OCH 1b, a potential therapeutic candidate for Th1-mediated autoimmune diseases, is described. The synthesis incorporates direct alkylation onto epoxide 5 and stereospecific halide ion catalyzed alpha-glycosidation reaction. A key intermediate 10 was obtained in only eight steps and 37% overall yield from commercially available d-arabitol 2, and the total synthesis of 1b was accomplished in 12 steps and 19% overall yield. This method will enable the synthesis of a variety of phytosphingolipids, especially that with the shorter sphingosine side chain than 1a, in a highly stereoselective manner.
Assuntos
Glicoesfingolipídeos/síntese química , Imunossupressores/síntese química , Conformação MolecularRESUMO
Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.