RESUMEN
The synthesis and structure-activity relationships of a novel series of 3-aminothieno[2,3-b]pyridine-2-carboxamides were explored. Our efforts were focused on modifying the C-4 substituent of the thienopyridine ring to develop orally available bone anabolic agents. 4-Alkoxy derivatives were found to be novel ALPase enhancers without inhibitory effect on P450 activity. Among these derivatives, compound 6k was orally administered to ovariectomized rats, and it was found to significantly improve areal bone mineral density at a dose of 30â¯mg/kg/day.
Asunto(s)
Fosfatasa Alcalina/uso terapéutico , Osteoporosis/tratamiento farmacológico , Piridinas/síntesis química , Fosfatasa Alcalina/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
Atrial natriuretic peptide (ANP) exerts beneficial pharmacological effects in the treatment of various cardiovascular disorders, such as acute congestive heart failure (ADHF). However, the clinical use of ANP is limited to the continuous intravenous infusion owing to its short half-life (2.4 ± 0.7 min). In the present study, we conjugated the glyco-modified ANP with a monoclonal antibody (mAb) or an Fc via chemo-enzymatic glyco-engineering using EndoS D233Q/Q303L. The most potent derivative SG-ANP-Fc conjugate extended the half-life to 14.9 d and the duration of blood pressure lowering effect to over 28 d. This new biologic modality provides an opportunity to develop outpatient therapy after ADHF.
Asunto(s)
Factor Natriurético Atrial/farmacología , Factor Natriurético Atrial/farmacocinética , Animales , Anticuerpos Monoclonales/química , Factor Natriurético Atrial/síntesis química , Factor Natriurético Atrial/química , Células CHO , Cricetulus , GMP Cíclico/agonistas , GMP Cíclico/sangre , Glicosilación , Semivida , Humanos , Inmunoconjugados/sangre , Macaca fascicularis , Masculino , Ratas , Ratas WistarRESUMEN
With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys.
Asunto(s)
Fructosa-Bifosfatasa/antagonistas & inhibidores , Fructosa-Bifosfatasa/metabolismo , Glucosa/antagonistas & inhibidores , Organofosfonatos/farmacología , Profármacos/farmacología , Administración Oral , Animales , Glucemia/metabolismo , Células Cultivadas , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Fructosa-Bifosfatasa/química , Hepatocitos/metabolismo , Humanos , Macaca fascicularis , Modelos Moleculares , Organofosfonatos/síntesis química , Organofosfonatos/química , Profármacos/síntesis química , Profármacos/químicaRESUMEN
For the purpose of reducing the strong CYP3A4 inhibitory potency of diamide prodrug 4, cyclic prodrugs of tricyclic-based FBPase inhibitors were synthesized. Extensive SAR studies led to the discovery of pyridine-containing cyclic prodrug 20, which strongly inhibited glucose production in monkey hepatocytes and also showed weak CYP3A4 inhibitory potency.
Asunto(s)
Alanina/análogos & derivados , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos/química , Organofosfonatos/química , Profármacos/química , Piridinas/química , Tiazoles/química , Alanina/síntesis química , Alanina/química , Alanina/farmacología , Animales , Células Cultivadas , Cristalografía por Rayos X , Citocromo P-450 CYP3A/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Haplorrinos , Conformación Molecular , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
Cerebral amyloid-beta peptide (Abeta) clearance plays a key role in determining the brain level of Abeta; however, its mechanism remains unclear. In this study, we investigated cerebral Abeta clearance across the blood-brain barrier (BBB) by using the Brain Efflux Index method. [125I]Abeta(1-40) was eliminated from rat brain to circulating blood with a half-life of 48.8 min and a half-saturation concentration of 8.15 nm. The Abeta(1-40) elimination rate was reduced by 30.5% in 23-month-old rats compared with 7-week-old rats. The intact form of Abeta(1-40) was detected in plasma after intracerebral administration, indicating the occurrence of efflux transport of intact Abeta(1-40). The Abeta(1-40) elimination rate was significantly inhibited by coadministration of 100 microg/ml insulin and 1 mm thiorphan by 44.6 and 34.0%, respectively. The level of intact [125I]Abeta(1-40) in the brain was increased by coadministration of insulin. Among insulin-degrading enzyme inhibitors, bacitracin inhibited the elimination rate, whereas N-ethylmaleimide and metal chelators had no effect. Receptor-associated protein, fucoidan, 3-bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile, anti-IGF-I receptor antibody, and l-tyrosine did not affect the Abeta(1-40) elimination rate, suggesting that the relevant receptors or transporters are not likely to be involved in the clearance. In conclusion, the present study has demonstrated the involvement of a proteolytic degradation process and an insulin-sensitive process in cerebral Abeta(1-40) clearance in the rat.