RESUMO
We observe a large magnetocaloric effect in monodisperse Ni and Ni(core)Ag(shell) nanoparticles in the superparamagnetic region. The organically passivated Ni nanospheres show a large magnetic entropy change of 0.9 J kg(-1) K for a 3 T magnetic field change. In comparison to the surfactant-coated Ni nanoparticles, the Ni(core)Ag(shell) nanoparticles show an enhanced coercivity, magnetization, and magnetocaloric effect (1.3 kg K for a 3 T magnetic field change). The coercivity at 10 K increases from 360 Oe for Ni nanoparticles to nearly 610 Oe for Ni(core)Ag(shell) particles. This large enhancement is attributed to the enhanced inter-particle interaction, which is mediated by the metallic shell, over the relatively weaker dipolar interaction in the surfactant-coated Ni nanoparticles, and to modification of the surface spin structure.
RESUMO
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
Assuntos
Inibidores de Adenosina Desaminase , Inibidores da Dipeptidil Peptidase IV , Glicoproteínas/antagonistas & inibidores , Hipoglicemiantes/síntese química , Piridinas/síntese química , Pirrolidinas/síntese química , Adenosina Desaminase/química , Administração Oral , Animais , Sítios de Ligação , Células CACO-2 , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/química , Cães , Feminino , Intolerância à Glucose/tratamento farmacológico , Glicoproteínas/química , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Macaca fascicularis , Modelos Moleculares , Estrutura Molecular , Piridinas/farmacocinética , Piridinas/farmacologia , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
