RESUMO
OBJECTIVES: Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1- (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment. METHODS: We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period. RESULTS: AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction from placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) from placebo. AT-7687 treatment was well tolerated and not associated with any side effects. CONCLUSIONS: This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.
RESUMO
Novel photoaffinity labeled fusidic acid analogues were obtained by a synthetic sequence employing a Wittig reaction between a fusidic acid aldehyde and benzyl bromides in the key step. Three commonly used photoreactive groups, benzophenone, trifluoromethyldiazirine, and aryl azide, were used. The photoaffinity labeled fusidic acid analogues demonstrated a potent antibacterial activity (MIC 0.016-4 microg/mL) and therefore represent a potential tool for the elucidation of the interactions between fusidic acid and its receptor EF-G.
Assuntos
Antibacterianos/síntese química , Azidas/síntese química , Benzofenonas/síntese química , Diazometano/análogos & derivados , Diazometano/síntese química , Ácido Fusídico/análogos & derivados , Ácido Fusídico/síntese química , Marcadores de Fotoafinidade/síntese química , Marcadores de Fotoafinidade/farmacologia , Antibacterianos/farmacologia , Azidas/farmacologia , Benzofenonas/farmacologia , Corynebacterium/efeitos dos fármacos , Diazometano/farmacologia , Ácido Fusídico/farmacologia , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
[reaction: see text] Alkyl nitrones undergo radical addition reactions to a series of alpha,beta-unsaturated amides and esters when subjected to samarium diiodide via a nitrogen equivalent to a ketyl radical anion. This reaction conveniently provides access to a variety of functionalized gamma-amino acids. The methodology was extended to the asymmetric synthesis of 4-substituted gamma-amino acids, via the nitrone radical addition reaction to acrylates/amides possessing a chiral auxiliary.
Assuntos
Aminoácidos/síntese química , Amidas/química , Ésteres/química , Radicais Livres/química , Iodetos/química , Óxidos de Nitrogênio/química , Samário/químicaRESUMO
Aromatic alpha-heterosubstituted thioesters were found to undergo radical 1,4-addition reactions to a series of alpha,beta-unsaturated amides and one ester when subjected to the single electron reducing agent, samarium diiodide, at -78 degrees C. These thioesters derived from alpha-amino acids represent a synthetically useful synthon of unstable acyl radicals. This reaction conveniently provides access to gamma-ketoamides and esters in yields up to 90%, structures that are common in various protease inhibitors derived from peptides. Examples with acryloyl and methacryloyl derivatives of alpha-amino acids and dipeptides lead directly to tri- and tetrapeptide mimetics possessing the gamma-ketoamide functionality. No epimerization was observed with the mild conditions used for these reactions.